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Inducing long term low latent inhibition

Inducing long term low latent inhibition

From what I have gathered of low latent inhibition, it is an extreme increased level of dopamine in the brain… dopamine is a neurotransmitter and hormone.

Increasing it has many advantages and a few nasty disadvantages.

While improving concentration, mood, energy, and libido for starters, too much can cause side effects such as addiction and a host of mental disorders. (schizophrenia and bipolar to name two)

I'm looking for those who might have more knowledge of the subject than I do: there is a lot of controversy over the internet and half of it can't be believed. So, for the question part:

1. Is increased dopamine levels the source (or at least main source) of LLI?

2.Is Dopamine increased more through direct supplements such as DHA which supposedly affect Dopamine levels directly, or supplements such as L-Dopa which claim to affect the precursors?

I've done my own research and am still looking for answers to the benefits, risks, and induction of such to lower latentcy… just looking for others' knowledge and/or experiences.


Low latent inhibition is not an ideal state… Wikipedia lists several potential problems including attentional and emotional dysregulation, psychosis, and negative emotionality. Wikipedia also suggests that intelligence may moderate effects on well-being, such that more highly intelligent people could cope with stronger stimulation more effectively, and possibly enhance creativity (Carson, Peterson, & Higgins, 2003).

As for dopamine, there's a lot to read and thoroughly reconsider before going ahead with any attempt to alter it. The dopamine hypothesis of schizophrenia is one particularly noteworthy concern with heightened dopamine levels; nausea is another risk, and addiction to the means of alteration is another. I don't know that this last risk is any less serious with legal drugs, or even naturally rewarding behaviors.

That being said, some regulated drugs are prescribed for disorders of low dopaminergic activity, including Parkinson's and (to some extent) attention-deficit hyperactivity disorder, including $_mathbf L$-DOPA and methylphenidate. I link here to the overdose sections to emphasize that using them is not a good idea without a strong recommendation from a doctor in support and supervision of medicinal use. Even those with severe disorders who basically need these medications may suffer complications, so the likelihood of normally functioning individuals benefitting safely from (ab)use of these drugs is rather low at best.

BTW, @ChuckSherrington's comment is wisely made, and I want to emphasize also that I'm only mentioning these drugs because they exist and are sometimes prescribed for disorders that sometimes result from harmfully low dopamine levels. These medications should NOT be used by normally functioning individuals. They have several undesirable side effects, and could be particularly dangerous if used to deliberately elevate dopamine receptor activity above normal. Beside that, many if not most are regulated substances, and illegal to use without a prescription.

This is not a place to look for people who have experimented with dopaminergic drugs on normally functioning individuals: such experimentation is dangerous and unethical, especially if conducted in an uncontrolled manner without professional medical support on hand. Personal use of a drug like $_ m L$-DOPA or methylphenidate without a prescription is not experimentation in a scientific sense, but is abuse in a legal sense.

Some properly ethical and cautious research has investigated the effects of various dopaminergic drugs on normal populations, and results seem mixed at best, and quite scary at worst. As a near-worst case, consider cocaine: it acts on much more than dopamine, and tends to dysregulate it, not just temporarily block its reuptake. These aspects make it a very messy way of manipulating dopamine, and leads to some of its well-known dangers. This may be an extreme example, but one shouldn't assume so; any psychoactive drug has some potential to upset homeostasis in a lasting way and in more ways than one intends.

Methylphenidate might be a near-best case pharmacodynamically, but it too affects more than just dopamine, and has its share of dangers, as I mentioned above. What makes it noteworthy is the debate surrounding it as a potential nootropic vs. drug of abuse. Here's an interesting excerpt from Wikipedia:

Methylphenidate is sometimes used by students to enhance their mental abilities, improving their concentration and helping them to study. Professor John Harris, an expert in bioethics, has said that it would be unethical to stop healthy people taking the drug. He also argues that it would be "not rational" and against human enhancement to not use the drug to improve people's cognitive abilities.[97] Professor Anjan Chatterjee however has warned that there is a high potential for abuse and may cause serious adverse effects on the heart, meaning that only people with an illness should take the drug. In the British Medical Journal he wrote that it was premature to endorse the use of Ritalin in this way as the effects of the drug on healthy people have not been studied.[98][99] Professor Barbara Sahakian has argued that the use of Ritalin in this way may give students an unfair advantage in examinations and that as a result universities may want to discuss making students give urine samples to be tested for the drug.[100][Emphasis added.]

Evidently there are cases to be made for both perspectives on methylphenidate, and a variety of ramifications to consider. More research would be helpful, especially for the sake of isolating important mechanisms of action and reducing undesirable side effects. Until that much is done successfully, methylphenidate seems too controversial to recommend at best, and downright dangerous to recommend at worst. Furthermore, being a Schedule II drug in USA, it is illegal to possess or distribute without prescription.

Another notable prospect of sorts (though still Schedule II) is buproprion. From Wikipedia:

The primary pharmacological action of the drug is as a mild dopamine reuptake inhibitor and also a much weaker norepinephrine reuptake inhibitor as well as a nicotinic acetylcholine receptor antagonist…

According to the US government classification of psychiatric medications, bupropion is "non-abusable".[93] In animal studies, squirrel monkeys and rats could be induced to self-administer bupropion, which is often taken as a sign of addiction potential; however, there are significant interspecies differences in bupropion metabolism.[54] There have been a number of anecdotal and case-study reports of bupropion abuse, but the bulk of evidence indicates that the subjective effects of bupropion are markedly different from those of addictive stimulants such as cocaine or amphetamine.[94] However bupropion is reported to be abused in Canada.[95]

One look at Tryon and Logan (2013) is more than enough to tell that the US government is wrong yet again on drug abuse; this one can definitely be abused in a really unsettling way (seriously, view at your own risk; it's got some gruesome imagery). However, to be fair, I can't verify that the cited source for the US government [93] says "non-abusable"; the link only leads to a table where bupropion is listed underLow Abuse Potential… but this seems pretty outdated in light of the news from Canada, unfortunately. Granted, this is primarily a problem with intravenous administration, which is not intended… but clearly the potential exists, and is bad enough to outweigh any merits of deregulation I could imagine. Again, further demonstration of how hazardous this psychopharmacological minefield of dopaminergic drugs really is… The only safe advice is to steer clear - barring any exigent need and prescription for personal medical use, of course - but that doesn't apply here.

References
- Carson, S. H., Peterson, J. B., & Higgins, D. M. (2003). Decreased latent inhibition is associated with increased creative achievement in high-functioning individuals. Journal of Personality and Social Psychology, 85(3), 499-506. Retrieved from ResearchGate.
54. Dwoskin, L. P., Rauhut, A. S., King‐Pospisil, K. A., & Bardo, M. T. (2006). Review of the pharmacology and clinical profile of bupropion, an antidepressant and tobacco use cessation agent. CNS Drug Reviews, 12(3-4), 178-207.
93. Center for Substance Abuse Treatment. (2000). Abuse potential of common psychiatric medications. In Substance abuse treatment for persons with HIV/AIDS (Treatment Improvement Protocol (TIP) Series, No. 37, pp. 83-84). Rockville, USA: Substance Abuse and Mental Health Services Administration. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK64916/table/A67504/.
94. Lile, J. A., & Nader, M. A. (2003). The abuse liability and therapeutic potential of drugs evaluated for cocaine addiction as predicted by animal models. Current Neuropharmacology, 1(1), 21-46.
95. Tryon, J., & Logan, N. (2013, September 18). Antidepressant Wellbutrin becomes 'poor man's cocaine' on Toronto streets. Global News: Health. Retrieved from http://globalnews.ca/news/846576/antidepressant-wellbutrin-becomes-poor-mans-cocaine-on-toronto-streets/.
97. Harris, J. (2009). Is it acceptable for people to take methylphenidate to enhance performance? Yes. British Medical Journal, 28(8), b1955. Retrieved from http://livingtomorrow.livejournal.com/59100.html.
98. Chatterjee, A. (2009). Is it acceptable for people to take methylphenidate to enhance performance? No. British Medical Journal, 338, b1956. Retrieved from http://repository.upenn.edu/cgi/viewcontent.cgi?article=1079&context=neuroethics_pubs&sei-redir=1.
99. BBC News. (2009, June 19). Ritalin backed as brain-booster. Retrieved from http://news.bbc.co.uk/2/hi/health/8106957.stm.
100. Davies, C. (2010, February 21). Universities told to consider dope tests as student use of 'smart drugs' soars. The Observer: Education: Student Health. Retrieved from http://www.theguardian.com/society/2010/feb/21/smart-drugs-students-universities.


I have to agree with @NickStauner - it sounds like you (as most people do; television is a culprit here) have a relatively rose-tinted view of people with a lower latent inhibition.

This is not an answer, this is an anecdote.

First off, a person's 'level of latent inhibition' will fluctuate. I have low latent inhibition (if you read this - yep, that's a description of me), but it changes from day to day.

On good days, great days, having this is one of the best blessings anyone could have (in my opinion, of course). I can attend to - entirely literally and without exaggeration - everything in my visual/aural sensory field (and if it's an awesome day, all at the same time). I'm aware of everything around me, down to the insects within a few feet. My brain registers and tracks everything and nothing escapes my senses.

On bad days, this is a curse. Yes, it's cliched, but it's true. On bad days, I'm not tracking anything… but I am registering it. Everything. I know people with ADD/ADHD, and on bad days I'm almost exactly like them. And the worst days, it happens over and over and over again. Imagine driving, except that you don't just see the things around you - you see the things around you again, and again, and again, and again. It's not that you don't remember, it's just that your brain temporarily says, "hey, wait, what's that, that's new… oh wait, no, it's not… oh hey!"

Most days are somewhere in between. Thankfully, there's a lot I can do - sleeping properly, eating properly, and exercise have no substitutes!

Now for more anecdotal stuff:
I've found that inducing a 'flow' state improves my ability to handle this sensory deluge. Music, and certain activities (there are a number of questions on CogSci.SE about the flow state) in particular. Trance-inducing activities and meditations also help. Certain binaural beats also help.

This, again, isn't an answer. I don't know how to induce this state in others. Drugs… don't really work, as far as I can tell - at least not the ones around currently. Stimulants have too many side effects, or are too strong, or cause too strong of focus, or in general overshoot their target most of the time. Classic stimulants, such as ADHD drugs, definitely don't induce this state.

I will say this: by and far, if you want it, then do it:

  • Pay attention to everything. Make yourself pay attention to everything. Register everything in your sensory fields. As soon as you register something, register something else. If something moves, register it. If something makes a sound, isolate, orientate to, and register it.
  • Then make yourself question everything - why is anything the way it is? This is not about actually answering, but about making your brain work differently. Do this constantly, all the time, it's all that exists to you: registering and analyzing everything. Verify everything afterwards, but go as far as you can, then go as fast as you can. Be correct before you're fast (this is reallllly important. If you're fast but incorrect, you start to believe in supernatural events. Sounds ridiculous, but… well, anecdotally true, at least).
  • Push yourself to do it faster, faster, faster.

Now here's the problem - you're trying to do this from the top-down. There are things you won't be able to induce, things that may, or may not, eventually appear on their own:

  • Automatically orientating on new sensory stimuli. As mentioned, if something moves, I know it's there; no exceptions. A spider could move in the very corner of my peripheral vision, and I'd have registered it. That said, I don't necessarily know what moved, but I know that something moved. When I'm tired though, there are a lot of false positives. If I go for long enough with little enough sleep, I'll start to see shadows move. This is NOT fun.

  • Automatically knowing something is different. This isn't conscious, nor is it specific. If you've gotten new glasses, or a new haircut, or changed something else, I'll know something is different (again, most days). But it might take me a bit to figure out what the difference is. Chances are, I'll be looking at you funny while trying to figure it out.

  • Reading non-physical 'energies' around me. This one is… so hard to grasp and explain. I don't fully understand it, so explaining it is difficult. It's a 'soft focus' where I'm not truly paying attention to any one thing. Instead, I'm watching (again) everything at the same time. If I'm in a room with people, I know when things will happen before they do. I know if people are bored, or angry, happy, or jealous. I know if people are hiding something, or if they need to share. I can read the stress in your voice and I can know from the way that you're holding yourself that you slept poorly last night. Some of this is the LLI, but there's another half of it:

  • Read everything. Everything. Nothing is possible if you don't understand how it all fits together. Read about people especially, and how people work - individually, in isolation, in groups, as followers, as leaders, and when they're interacting with others. Read about physics to understand exactly how to throw the skeeball (with the proper 'soft focus'/'not trying') to get the 100.

  • (Learn to) Juggle. I don't have a link with me, but juggling improves your brain in many different ways.

  • And lastly, always always always (x 1000) do the Big 3: eat properly, sleep properly, and exercise properly.


Now, given all that - THIS IS NOT AN ACCEPTABLE ANSWER, SO DON'T ACCEPT IT (if you do, I'll make it CW and give it away anyway). I have no sources, no citations, and no backup. I have nothing but anecdotal evidence, and this is the internet. You shouldn't trust me even if I did - almost anything can be skewed to support anything else.

If you want LLI, start to figure everything out for yourself!


4. Discussion

4.1. Summary and validity of the findings

The goal of this study is to further characterize behavioral memory induced by pairing a tone with stimulation of the cholinergic nucleus basalis. This line of research was initiated by the discovery that tone paired with stimulation of the nucleus basalis induced CS-specific shifts of frequency receptive fields in the primary auditory cortex (Bakin & Weinberger, 1996). Subsequently, several laboratories replicated and extended this finding, all within a framework of cholinergic mechanisms underlying learning and memory (e.g., Chen & Yan, 2007 Kilgard & Merzenich, 1998 Moucha et al., 2005 Zhang, Hamilton, Nathanson, & Yan, 2006). Although extensive pharmacological studies had, and continue to, implicate the cholinergic system in learning and memory, they are limited in the ability to pinpoint specific cholinergic neural structures or circuits and to actually induce memory. Thus, such nucleus basalis stimulation studies are valuable in their ability to locate critical cholinergic loci. However, demonstrations of NB-induced specific plasticity provide a presumptive, rather than a direct, link between the cholinergic system and actual memory. Even granting that specific associative plasticity is at least part of a substrate of memory, a general tendency to more-or-less equate learning-related neural plasticity with memory can be considered to constitute a �tegory error”, i.e., attribution to a part the properties of the whole (Ryle, 1949). Thus, the rationale for determining if NB stimulation can induce behavioral memory, as opposed merely to inducing neural plasticity, is that allegations of cholinergic sufficiency for memory formation can be directly tested.

If activation of the NB during natural learning is sufficient to induce memory, as well as neural plasticity, then appropriately-timed direct stimulation of the NB should be sufficient to also induce memory. Moreover, NB-induced associative memory should have major characteristics of natural associative memory. Previous experiments had revealed that this type of memory is associative, highly specific, rapidly acquired, can be induced in a single session, becomes more precise over time (𠇌onsolidates”) and is retained for at least several days (Introduction see also Weinberger, 2007 Weinberger et al., in press). They also revealed that the NB-induced memory does require the engagement of muscarinic cholinergic receptors (Miasnikov et al., 2008b). The current study examined experimental extinction and the effects of CS and NBstm unpaired pre-exposure (i.e., potential effects of LI/LIRR, latent inhibition or learned irrelevance).

4.2. Extinction

It is now almost universally agreed that behavioral extinction indexes the learning of a new “inhibitory” contingency rather than the loss of the original association. Such inhibitory learning is itself both expressed by the reduction of response to the CS and by its ability to interfere with new learning to the CS (Bouton, 2007 Mackintosh, 1974). Thus, extinction is indicative of the flexibility of mnemonic processes in adjusting behavior to changing circumstances. The current findings show that after pairing a tone with stimulation of the NB in the IP group, which induces specific associative memory, disrupting the initial contingency produces a loss of frequency-specific response. We interpret this change in behavior as indexing experimental extinction as it encompasses the key elements of extinction, i.e., elimination of the contingency between the CS and NBstm. However, the procedures that we employed are different from standard extinction protocols, in which the US is simply absent while the CS continues to be presented. Instead of removing the NBstm, which is a proxy for the US, we retained the “US” but removed its ability to be predicted by the CS tone.

Our rationale was twofold. First, this permitted a balanced design with the IU group so that both groups experienced the same stimuli in both phases of the experiment, undergoing only a change in the CS–NBstm relationship. Second, and generally overlooked, is the fact that removal of the US also produces a change in the state of subjects. For example, removing a shock US in fear conditioning also reduces the arousal level of the animals. We wished to avoid this confound, not only because it complicates the interpretation of the results, but because it would lead to grossly different levels of ACh released into the cerebral cortex, including the auditory cortex. There is close relationship between arousal level and the level of ACh in the cortex, the greater the arousal, the greater the level of ACh (e.g., Cape & Jones, 1998, 2000 Celesia & Jasper, 1966 Metherate, Cox, & Ashe, 1992 Phillis, 1968 Phillis & Chong, 1965 Rasmusson & Szerb, 1976). Therefore, removing NBstm from the IP group during the second phase of the experiment would have had a detrimental consequence: subjects’ lowered arousal level would have meant that comparisons between the IP and IU groups during the second phase would engender a confound in arousal level, so that any differences in behavior could not be attributable exclusively to the training contingencies.

That the IP group exhibited behavioral extinction when its contingency was changed indicates that NB-induced memory possesses another important attribute of natural associative memory. This finding adds to the evidence that engagement of the NB during normal learning is sufficient to induce natural associative memory. That NB-induced memory possess attributes of natural memory is important because it reduces the possibility that induced memory is simply a demonstration of what the brain can be 𠇏orced to do” by an intervention such as electrical microstimulation. We do realize that in principle, one could examine all associative phenomena to determine if NB-induced memory has all of the attributes of normal associative memory. However, we believe that this would not be a good strategy, and address this issue in the final section of this paper.

4.3. Effect of pre-exposure to unpaired tone and NBstm

The IU group first received tone and NBstm in unpaired and later received them in a standard, paired relationship. This constitutes pre-exposure to both the CS and the “US”, i.e., NBstm which was presented at the time that a standard US ordinarily would be given. With reference to such “proxy” status, it is important to note that NBstm that induces specific associative memory is motivationally neutral, i.e., it has neither positive nor negative valence (Miasnikov et al., 2008a) although it can elicit changes in respiration and heart rate (McLin, Miasnikov, & Weinberger, 2002b). Thus, the current experiment is not merely a demonstration that brain stimulation which is appetitive or aversive can serve as a US, as it is often used in tracing a conditioning circuit (e.g., Chapman, Steinmetz, & Thompson, 1988 Cruikshank, Edeline, & Weinberger, 1992 Steinmetz, Lavond, & Thompson, 1989). Rather, it is a test of a particular model of natural sensory associative learning, which posits a 𠇏inal common path” for the long-term, specific storage of information via activation of the nucleus basalis, its release of ACh into the auditory cortex and the subsequent engagement of cholinergic receptors in the auditory cortex (Weinberger, 1998, 2007).

Pre-exposure to a CS generally retards subsequent acquisition to that stimulus, a process known as “latent inhibition” (e.g., Lubow & Moore, 1959). Less well known, but also established, are the effects of exposure to the US prior to attempting conditioning. This “US pre-exposure effect” also is indexed by retardation of acquisition, when the US is later used in conditioning (Kremer, 1971).

Additionally, retardation of learning when there is pre-exposure to both the CS and US has been interpreted as “learned irrelevance” (LIRR). (e.g., Baker, 1976 Baker & Mackintosh, 1977 Bennett, Maldonado, & Mackintosh, 1995). However, LIRR has been disputed other workers have been arguing that the CS/US pre-exposure effect can be explained by recourse to the sum of latent inhibition and the “US alone pre-exposure effect” (e.g., Bonardi & Hall, 1996 Bonardi, Hall, & Ong, 2005 Bonardi & Ong, 2003). Regardless of the ultimate theoretical explanation of the effects of CS and US unpaired pre-exposure on later associative learning, the role of the NB is of interest, at the very least with reference to the characteristics of natural associative memory. If the pre-exposure effect were found with CS/NBstm pre-exposure, then there might be a neural link between a specific brain structure and several important psychological problems.

Group IU received about 200 presentations each of tone and NBstm (i.e., CS and “US”) alone prior to their pairing when the contingencies were reversed in the second phase of the experiment, thus potentially producing LI/LIRR due to pre-exposure to the CS, the “US” or both.

The present study does provide modest support for the pre-exposure effect using tone and NB stimulation. First, the magnitude of CS band conditioned responses was smaller in the IU group than in the IP group, specifically 42% of the latter group ( Fig. 3 ). However, this effect was not statistically significant, therefore it should not be given undue weight. Second, the S–T analysis of response latencies ( Fig. 5 ) demonstrates that the pre-exposure to unpaired stimulation eliminated the early components of conditioned responses following subsequent pairing, delaying associative behavior several seconds (e.g., Fig. 4C and F ). The early component is ordinarily well-developed following training in naïve subjects Fig. 4B and E ). In addition, the pre-exposure retardation of acquisition was specific to the CS band, a degree of specificity that has not been reported previously. However, whether the current effects are due to latent inhibition or learned irrelevance cannot be determined from the present study.

4.4. Spectro-temporal patterns of associative responses

As noted, CS-specific associative memory developed both in the IP group in initial training and in the IU group after contingency reversal. However, spectro-temporal analyses of associative responses revealed a different latency of associative responses. This associative latency effect would not have been detected had analysis been limited to the 2-s period of tone presentation. Rather, it might have been concluded that pre-exposure of the IU group to the CS and NBstm unpaired had produced little associative response.

These findings demonstrate in general the importance of employing behavioral analyses that are sufficiently sensitive to avoid a Type II error. Thus, while such pre-exposure did not appear to retard subsequent acquisition of processing of frequency information, the significant increase in response latency may indicate the involvement of additional processing resources. Thus, the IU group may have had to overcome presumptive prior learning that the CS predicted nothing, so that suppression of this knowledge may have required an extra step before the new association could become manifest. Such “on-line” behavioral tracking could prove useful in pursuing networks of neurons engaged in the formation of specific memories.

4.5. Future directions for NB-induced associative memory

The current study has demonstrated that specific, associative behavioral memory that is induced by stimulation of the nucleus basalis exhibits experimental extinction. However, it is moot regarding latent inhibition, probably because of the use of physiologically-potent NBstm, which is neither sensory nor motivational in character. These findings raise the issue of how many characteristics of natural memory should be found to also occur for NB-induced memory? For example, should latent inhibition be re-studied by presenting tone alone before pairing it with NBstm? We have explained above our rationale for the current design of maintaining the same overall density of tone and NBstm throughout the study. Innumerable other associative phenomena could be studied as well (Bouton, 2007). At what point is the specter of 𠇍iminishing returns” attained? We suggest that this point may now have been reached. NB-induced memory has been shown to possess key attributes of natural associative memory: associativity, specificity, rapid acquisition, consolidation, long-term (days) retention and now experimental extinction.

NB-induced memory also permits a 𠇍issection” of memory processes. It does not involve motivational and emotional processes thus, aspects of “pure” associative processes can be studied neurobiologically. For example, now that NB-induced memory has been shown to be very similar to natural memory, it would be appropriate to determine the neural effects and the neural networks that enable NBstm to produce associative memory. Another advantage of NB-induced memory is that it provides a way to understand the contents of memory, because the level of activation controls the level of detail that is encoded, stored and retrieved low levels of activation produces association without frequency specificity (𠇏lat” generalization gradients), whereas moderate levels of activation produce both associativity and specificity (“sharp” generalization gradients with a peak at the CS frequency band) (Weinberger et al., 2006).

Finally, a third line of inquiry that is now possible given the known attributes of NB-induced memory is that of investigating the behavioral use of the embedded information. For example, suppose a subject has “learned” that an 8.0 kHz tone is important because it has been paired with NBstm, although the tone likely signifies importance without serving as a signal for anything. Nonetheless, if 8.0 kHz is now behaviorally pre-potent, then the subject should be more likely to pay attention when it encounters this stimulus in a new setting, in the absence of NBstm. The heightened salience of this tone should have predictable consequences if indeed NB-induced memory involves the encoding of information in the same sense that natural learning does, e.g., the importance of the CS frequency. This information should be capable of facilitating new learning or the solution of a completely novel problem. This outcome would serve as the first validation that specific information can be directly “inserted” into the brain.


Brain Research in Addiction

Samantha J. Brooks , . Dan J. Stein , in Progress in Brain Research , 2017

1.1 Broad Definitions of Impulsivity/Compulsivity

Previously, impulsivity and compulsivity were regarded as dissociable states underpinned by distinct neural mechanisms within the fronto-striatal network for sensation/risk seeking and aversion avoidance, respectively ( Dalley et al., 2011 Fineberg et al., 2014 ). However, neurobiological research since the advent of neuroimaging, has led to updated conceptualizations of impulsivity and compulsivity that broadly share common substrates within the fronto-striatal circuitry for high levels of automaticity, impaired cognitive inhibition , lack of self-control, and maladaptive self-regulation. Discrete differences in regional activation within this broad network may shed further light on the neural mechanisms of interaction between impulsivity and compulsivity that present as fluctuating symptoms for many mental disorders. For example, in SUD there appears to be a change from controlled drug use to habitual compulsivity over time (particularly in those with trait susceptibility for impulsivity), which is linked to Pavlovian-Instrumental Transfer (PIT) and a switch from ventral to dorsal striatum activation ( Brewer and Potenza, 2008 Everitt and Robbins, 2016 Robbins et al., 2012 ). Furthermore, fluctuations in impulsive and compulsive symptoms can occur within the individual that underpin comorbidity with other related psychiatric diagnoses (e.g., ADHD and OCRD), which also suggests variations in neuropathology across common brain circuits such as the fronto-striatal network, and possibly differences in genetic elements (e.g., single-nucleotide polymorphisms [SNP] and epigenetic effects). Therefore, it is pertinent to consider definitions of impulsivity and compulsivity that provides separate conceptualizations and whether interaction between them can be largely regarded as state (a behavior present only in certain contexts) or trait (a predisposition).


Results

Participants

No significant group differences were obtained for age, t(38) = 0.306, p = 0.761, intelligence, t(38) = 𢄠.973, p = 0.337, alcohol consumption, t(38) = 0.478, p = 0.521, or cannabis consumption, t(38) = 0.169, p = 1.00. Table 1 shows drug-use profiles for the two groups.

Stop-Signal Task

Analyses of mean RT to go signals showed that khat users (536 ms) tended to respond more slowly than khat-free controls (474 ms), but this difference was not significant, p > 0.055. The percentage of choice errors to go-signals was low and did not discriminate between khat users (1.8%) and khat-free users (1.0%, p > 0.30). SSRTs were computed for each participant and for each group separately. All participants were able to stop their responses successfully in about half of the stop trials (51.9% in khat users and 49.7% in khat-free controls), indicating that the dynamic tracking algorithm worked well in both groups. Most importantly, SSRTs were significantly longer for users (236 ms) than for non-users (192 ms), F(1,38) = 33.21, p < 0.001, MSE = 584.624, η 2 p = 0.47, see Figure 2. The group effect remained largely significant even after using RT to go signals as covariate, F(1,38) = 29.97, p < 0.001, MSE = 599.701, η 2 p = 0.44. To test whether the magnitude of cognitive impairments is proportional to the amount of khat consumed, we computed Pearson correlation coefficients between the individual lifetime khat exposure, hours chewing and number of bundles used in a khat session, and SSRT. No significant correlations were obtained, probably due to very little between-subject variability.

Figure 2. Mean SSRT (stopping latency) as a function of Group (khat-free controls vs. khat users). Vertical capped lines atop bars indicate standard error of the mean.


Results

Experiment 1: AMPA/nAChR interaction in latent inhibition

To examine the roles of nAChRs and AMPARs in latent inhibition of cued fear conditioning, mecamylamine alone, NBQX alone, or mecamylamine and NBQX together were given prior to pre-exposure to the CS (i.e., latent inhibition). It was expected that mecamylamine would not block latent inhibition, based on previous results (Gould et al. 2001). In addition, it was expected that NBQX would not alter latent inhibition based on a preliminary study (Gould and Lewis 2003) and based on results from an experiment that examined the effects of NBQX on fear conditioning (Lu and Wehner 1997). However, if nAChRs and AMPARs are mediating similar processes involved in latent inhibition, coadministration of the two drugs should abolish latent inhibition. A one-way analysis of variance revealed an overall effect of drug [F(4,37) = 11.04, P < 0.001]. Post-hoc analysis revealed significant differences between saline pre-exposed and saline non-pre-exposed groups (P < 0.05), with pre-exposed mice having higher suppression ratios compared with non-pre-exposed mice. This indicates the establishment of latent inhibition ( Fig. 1 ). If mecamylamine has no effect on latent inhibition, we would then expect this group to have suppression ratios that are significantly higher than saline non-pre-exposed mice and similar to saline pre-exposed mice. There were significant differences between mecamylamine pre-exposed and saline non-pre-exposed groups (P < 0.05), but no differences were observed between the mecamylamine pre-exposed mice and the saline pre-exposed mice (P > 0.05), suggesting that nAChRs antagonism alone does not block the establishment of latent inhibition ( Fig. 1 ). This result is consistent with a previous finding (Gould et al. 2001). Similarly, if NBQX has no effect on latent inhibition, we would then expect that the group-administered NBQX would have suppression ratios that are significantly higher than saline non-pre-exposed mice, but similar to saline pre-exposed mice. There were significant differences between NBQX pre-exposed and saline non-pre-exposed mice (P < 0.05), and no differences were observed between saline pre-exposed mice and NBQX treated pre-exposed mice (P > 0.05). This data suggests that AMPAR antagonism alone does not disrupt latent inhibition ( Fig. 1 ).

The effects of NBQX (30.0 mg/kg AMPAR antagonist), mecamylamine (1.0 mg/kg nAChR antagonist), or coadministration of the two drugs on latent inhibition of cued fear conditioning. There were significant differences between saline pre-exposed (Sal Pre) and saline non-pre-exposed (Sal No Pre) mice, indicating that latent inhibition was established. Neither NBQX (NBQX Pre) nor mecamylamine (Mec Pre) administered alone on pre-exposure day had any effect on latent inhibition. The coadministration of NBQX and mecamylamine on pre-exposure day (NBQX /Mec Pre) blocked latent inhibition of cued fear conditioning. Light gray bars represent pre-exposed groups. Dark gray bars represent non-pre-exposed groups. Error bars, ± SEM. ( * ) Significantly different from saline pre-exposed mice.

To examine the possibility that coantagonism of nAChRs or AMPARs could disrupt latent inhibition, mecamylamine and NBQX were coadministered prior to pre-exposure. If coantagonism of these two receptors blocks latent inhibition, we would then expect the suppression ratios for this group to be significantly lower than saline pre-exposed mice and similar to saline non-pre-exposed mice. Post-hoc analysis revealed significant differences between the mecamylamine/NBQX pre-exposed and saline pre-exposed groups (P < 0.05) and no differences were observed between the coadministration group and saline non-pre-exposed group (P > 0.05), indicating that the coantagonism of these receptors blocked the establishment of latent inhibition ( Fig. 1 ). The time to initiate the first lick of the testing trial was measured and compared between groups. A one-way ANOVA revealed no differences in lick latencies for any groups [F(4,37) = 0.802, P > 0.05]. Thus, drug conditions and preexposure conditions did not disrupt initiation of licking on testing day.

To examine the possibility that the lack of effect observed in both the NBQX pre-exposed and mecamylamine pre-exposed groups could have resulted from lasting effects of either drug administered on pre-exposure day that carried over to training day, NBQX or mecamylamine was administered to non-pre-exposed mice and compared with saline non-pre-exposed mice. A one-way ANOVA revealed no differences between saline non-pre-exposed mice and either NBQX or mecamylamine non-pre-exposed mice [F(2,21) = 1.297, P > 0.05], suggesting that neither NBQX nor mecamylamine had lasting effects on training day (data not shown).

Experiment 2: NMDA/nAChR interactions in latent inhibition

Activation of nAChRs can depolarize neurons (Roerig et al. 1997 Hefft et al. 1999) and also activate cell-signaling cascades by mediating calcium influx (Chang and Berg 2001 Nakayama et al. 2001 Berg and Conroy 2002 Dajas-Bailador et al. 2002b Utsugisawa et al. 2002 Brunzell et al. 2003). This ability of nAChRs to activate cell-signaling cascades similar to NMDARs suggests that nAChRs could interact with or perform a similar function to NMDARs during learning. To test whether nAChRs and NMDARs mediate similar processes, a dose of MK-801 subthreshold for disrupting fear conditioning (0.05 mg/kg, dose based on dose-response experiment) either alone or in combination with mecamylamine (1.0 mg/kg) was administered. A one-way ANOVA revealed an overall effect of treatment condition [F(3,36) = 9.20, P < 0.05]. Post-hoc analysis revealed significant differences between saline pre-exposed and saline non-pre-exposed (P < 0.05) mice, indicating latent inhibition was established ( Fig. 2 ). MK-801 pre-exposed mice were not significantly different from saline pre-exposed mice (P > 0.05) and were significantly different from non-pre-exposed mice (P < 0.05). These data suggest that this dose of MK-801 was ineffective at disrupting latent inhibition ( Fig. 2 ). If the coadministration of MK-801 and mecamylamine disrupts latent inhibition, we would then expect these mice to demonstrate suppression ratios similar to saline non-pre-exposed mice and significantly different from saline pre-exposed mice. Post-hoc analysis revealed that the group that received both antagonists demonstrated suppression ratios that were not different form saline non-pre-exposed mice (P > 0.05) and were significantly lower than saline pre-exposed mice (P < 0.05), demonstrating that the coadministration of MK-801 and mecamylamine disrupted latent inhibition of cued fear conditioning ( Fig. 2 ). There was a significant effect of drug on latency to first lick [F(3,36) = 5.89, P < 0.05]. The MK-801 pre-exposed mice demonstrated longer latency to initiate the first lick on testing day (P < 0.05 for all comparisons). However, these mice demonstrated suppression ratios similar to saline pre-exposed mice, suggesting that this difference had little effect on the resulting suppression ratios on testing day.

The effects of MK-801 (0.05 mg/kg NMDAR antagonist), mecamylamine (1.0 mg/kg nAChR antagonist), or coadministration of the two drugs on latent inhibition of cued fear conditioning. There were significant differences between saline pre-exposed (Sal Pre) and saline non-pre-exposed (Sal No Pre) mice, indicating that latent inhibition was established. The coadministration of MK-801 and mecamylamine on pre-exposure day (MK/Mec Pre) blocked latent inhibition of cued fear conditioning. Light gray bars represent pre-exposed groups. Dark gray bars represent non-pre-exposed groups. Error bars, ±SEM. ( * ) Significantly different from saline pre-exposed mice.

Experiment 3: AMPA/nAChR interaction in fear conditioning

To examine the role of nAChRs and AMPARs in fear conditioning, mecamylamine alone, NBQX alone, or both drugs together were administered prior to training. It was expected that neither mecamylamine nor NBQX would block cued or contextual fear conditioning (Lu and Wehner 1997 Gould and Wehner 1999b), but coadministration of the two drugs would block contextual fear conditioning if AMPARs and nAChRs mediate similar processes involved in contextual conditioning. A one-way analysis of variance examining baseline freezing on training day revealed no differences between groups [F(5,41) = 0.51, P > 0.05] ( Fig. 3 ). A one-way analysis of variance performed on freezing to the context on testing day revealed an overall effect of drug [F(5,41) = 5.01, P < 0.01]. Post-hoc analysis revealed significant differences between the saline group and both of the mecamylamine and NBQX coadministration groups for contextual conditioning (P < 0.05 for both groups) ( Fig. 3 ).

The effects of NBQX (15.0 and 30.0 mg/kg), mecamylamine (1.0 mg/kg), or the coadministration of the two drugs on contextual fear conditioning. There were no differences in baseline freezing on training day for any of the groups. Neither NBQX nor mecamylamine administered alone had any effect on contextual fear conditioning on testing day when compared with saline controls. However, the coadministration of 1.0 mg/kg mecamylamine with 15.0 mg/kg or 30 mg/kg NBQX on training day significantly reduced contextual fear conditioning on testing day compared with saline controls, and to mice administered either drug administered alone. Error bars, ±SEM. ( * ) Significantly different from saline, NBQX 15mg/kg, NBQX 30 mg/kg, and Mecamylamine.

In addition to examining changes in contextual conditioning, changes in cued fear conditioning were also examined. A one-way analysis of variance performed on pre-CS freezing scores revealed no significant differences between groups [F(5,41) = 2.32, P > 0.05], suggesting no differences in generalized freezing. A one-way analysis of variance performed on freezing during the CS revealed no significant differences between groups [F(5,41) = 1.99, P > 0.05] ( Fig. 4 ) suggesting that mice coadministered mecamylamine and NBQX can process the CS and form a CS association with the footshock US.

The effects of NBQX (15.0 mg/kg and 30.0 mg/kg), mecamylamine (1.0 mg/kg), or the coadministration of both drugs on cued fear conditioning. There was no difference in pre-CS freezing between groups, and there was no significant effect of drug on freezing to the CS on testing day. Error bars, ±SEM.

To examine the possibility that freezing to the CS in the NBQX/Mec group was a result of nonassociative processes, mice received either saline or coadministration of mecamylamine and NBQX, and then received two presentations of the CS without the US. It was expected that these mice would not show fear to the context nor to the CS during subsequent tests. There were no differences between baseline freezing [F(1,6) = 0.273, P > 0.05], freezing to the context [F(1,6) = 0.429, P > 0.05], or freezing to the CS [F(1,6) = 0.097, P > 0.05] between groups (data not shown). These data suggest that freezing to the CS on testing day observed in mice coadministered mecamylamine and NBQX and trained in fear conditioning with CS–US pairings reflected the formation of a CS–US association.

Experiment 4: NMDA/nAChR interactions in fear conditioning

To further test whether nAChRs and NMDARs mediate similar processes during learning, we administered a subthreshold dose of MK-801 (0.05 mg/kg) either alone or in combination with mecamylamine (1.0 mg/kg). A one-way analysis of variance examining baseline freezing on training day revealed no differences between groups [F(3,36) = 0.22, P > 0.05] ( Fig. 5 ). A one-way analysis of variance performed on freezing to the context on testing day revealed an overall effect of drug [F(3,36) = 21.72, P < 0.01]. Post-hoc analysis revealed significant differences between the saline group and the MK-801/mecamylamine coadministration group (P < 0.05). No differences were observed between the saline and MK-801 alone groups, demonstrating that this dose of MK-801 was subthreshold for disrupting contextual fear conditioning. These results suggest that nAChRs may mediate similar processes as NMDARs during contextual fear conditioning.

The effects of MK-801 (0.05 mg/kg), or the coadministration (at either training day only or both training and testing) of MK-801 and mecamylamine (1.0 mg/kg) on contextual fear conditioning. There were no differences in baseline freezing on training day for any of the groups. MK-801 administered alone had no effect on contextual fear conditioning compared with saline controls. However, the coadministration of 1.0 mg/kg mecamylamine with 0.05 mg/kg MK-801 on training day, or on both training day and testing day, significantly reduced contextual fear conditioning on testing day compared with saline controls. Error bars, ±SEM. ( * ) Significantly different from saline.

To ensure that the deficits in contextual fear conditioning did not result from state-dependent effects, MK-801 and mecamylamine were also coadministered on both training and testing days. Post-hoc analysis revealed a significant difference in freezing to the context between the saline group and group that received MK-801 and mecamylamine at both training and testing groups (P < 0.05). There was no difference in contextual fear conditioning between mice that received MK-801 and mecamylamine only at training and mice that received MK-801and mecamylamine at both training and testing. Thus, no state-dependent effects were seen.

In addition to examining changes in contextual conditioning, changes in cued fear conditioning were also examined. A one-way analysis of variance performed on pre-CS freezing scores revealed no significant differences between groups [F(3,36) = 0.88, P > 0.05], suggesting no differences in generalized freezing. A one-way analysis of variance performed on freezing during the CS revealed a significant effect of drug [F(3,36) = 10.42, P < 0.05] ( Fig. 6 ). Post-hoc analysis revealed that the saline group did not differ from either the MK-801 group or the MK-801/mecamylamine coadministration group. However, the MK-801/mecamylamine training/testing group showed significantly less fear to the CS than the saline group.

The effects of MK-801 (0.05 mg/kg), or the coadministration (at either training day only or both training and testing) of MK-801 and mecamylamine (1.0 mg/kg) on cued fear conditioning. There was no difference in pre-CS freezing between groups, but there was a significant effect of drug on freezing to the CS on testing day. The effect was due to reduced freezing in the group that received MK-801 and mecamylamine at both training and testing. Error bars, ±SEM. ( * ) Significantly different from saline.


Latent inhibition mediates N1 attenuation to repeating sounds

This work was supported by NIBIB grant EB002011 to Gabriele Gratton and a G. Ellsworth Huggins Graduate Scholarship from the University of Missouri–Columbia Graduate School to Jeffrey J. Sable. The authors wish to thank Nelson Cowan for his input on this work.

Abstract

Sound repetition typically reduces auditory N1 amplitudes, more so at higher rates. This has been attributed to refractoriness of N1 generators. However, evidence that N1 attenuation is delayed 300–400 ms after the first occurrence of a repeated sound suggests an alternative process, such as inhibition, that requires 300–400 ms to become fully operational. We examined the N1 to trains of fixed-interval (100, 200, 300, 400 ms) tones for evidence of effects predicted by models of refractoriness and of latent inhibition. Regardless of interval, latency of the eliciting tone from train onset determined N1 amplitudes during the first 400 ms of the train, which decreased in this window. The results show that N1 attenuation cannot be due simply to refractoriness, which would elicit the smallest N1 to the second tone. An inhibitory neural circuit can account for these and previous results, and may be important to auditory perceptual processing.


Results

Latent Profile Analyses in the Community Sample

Model fit for solutions with 2𠄶 latent classes were examined (see Table 1). The Lo–Mendell–Rubin-adjusted LRT indicated that models with 2, 4, and 6 classes showed improved fit over those with one fewer class. Of these, the six-class solution was rejected because the best log-likelihood value was not replicated and two of the classes contained less than 5% of the sample. The four-class solution was ultimately selected as the best fitting model because it showed better discrimination among the classes (higher entropy value at 0.68) and a lower BIC value (2434.78) than the two-class solution. Individuals were then classified according to their most likely class membership. As illustrated in Supplementary Figure 1, the first class was characterized by low ratings on both Avoidance and Approach scales (class 1 [Low/Low] 24% of the sample), the second class was characterized by average Avoidance and average Approach ratings (class 2 [Average] 48% of the sample), the third class was marked by high ratings on Avoidance and average Approach (class 3 [High Avoid] 20% of the sample), and the fourth class reflected low ratings for Avoidance and high ratings for Approach (class 4 [High App] 8% of the sample).

Table 1. Model fit of the latent profile analysis in a community sample.

To explore the external correlates of these affective profiles, we examined how they differed on measures of motivation, distress tolerance, borderline personality features, mood and anxiety symptoms, and alcohol/drug use problems. Results of these analyses are presented in Table 2 and Figure 1. Probability of membership in the class characterized by low ratings on both of the RISQ affect scales (Low/Low) was associated with greater resilience to distress, lower mood and anxiety symptoms, fewer borderline personality features, and less behavioral inhibition and activation than membership in the other classes. Probability of membership in the class marked by distinctly high ratings on RISQ Avoidance motivation (High Avoid), in contrast, was associated with significantly lower distress tolerance than membership in the other three classes. Furthermore, membership in the High Avoid class was related to higher ratings of behavioral inhibition, mood and anxiety symptoms, borderline personality features, and alcohol/drug use than membership in the classes with low ratings on RISQ Avoidance (classes 1 and 4). In contrast, the probability of membership in the class characterized by high ratings selectively on RISQ Approach motivation (High Approach) was associated with greater behavioral activation (BAS) and lower anhedonic depression symptoms than the probability of membership in the classes marked by low to average ratings on RISQ Approach motivation (classes 1 and 2).

Table 2. External correlates of RISQ affective profiles in a community sample.

Figure 1. Probability of class membership correlations with external variables by RISQ affective profiles in a community sample.

Predictive Affect Profiles in the Prison Sample

Using the latent profile structure extracted from the community sample, we applied the four-class solution to the prison sample. Class 1 (Low/Low) characterized 30% of the sample, class 2 (Average) characterized 47% of the sample, class 3 (High Avoid) characterized 16% of the sample, and class 4 (High App) characterized 7% of the sample.

In terms of substance use, the probability of membership in the class marked by selectively high ratings on RISQ Avoidance (class 3) was associated with higher prior alcohol use symptoms and cannabis use symptoms than the classes characterized by low and average scores on the RISQ affect scales (classes 1 and 2, respectively). Next, in terms of criminal activity, probability of membership in the High Approach class was associated with higher total number of crimes and non-violent crimes than membership in the other classes. Probability of membership in the class marked by low ratings on both of the RISQ affect scales (class 1) was associated with higher total number of violent crimes than membership in class 2 or 3, though this relationship was largely driven by higher numbers of sex crimes in class 1. Finally, in terms of disciplinary violations within prison, the probability of membership in the High Approach class was associated with higher total number of disciplinary violations than membership in class 2. Probability of membership in the High Avoid class was associated with higher number of violations against persons than membership in class 2 but lower number of substance use violations than membership in classes with low and average ratings on the RISQ affect scales (classes 1 and 2). Further, probability of class membership in the Average class was associated with fewer total days in segregation as punishment for substance use violations than membership in classes marked by high avoid and approach, respectively (classes 3 and 4) (see Table 3 and Figure 2).

Table 3. External correlates of RISQ affective profiles in a prison sample.

Figure 2. Probability of class membership correlations with external variables by RISQ affective profiles in a prison sample.


LONG-TERM DEPRESSION IN THE CEREBELLUM, HIPPOCAMPUS, AND NEOCORTEX

Long-term depression (LTD) is a type of synaptic plasticity in which the efficacy of signal transmission across a synapse is persistently reduced after a certain triggering activity. LTD in the cerebellum was proposed as a theoretical possibility around 1970 and was detected a decade later (Ito, Sakurai, and Tongroach, 1982). So far, several subtypes of LTD varying in cellular and molecular mechanisms have been found in the cerebellum, hippocampus, and neocortex. LTD occurs not only in excitatory synapses, but also in inhibitory ones. LTD may weaken or functionally interrupt useless or erroneous synaptic connections between neurons, providing an opposing mechanism against long-term potentiation (LTP) in various forms of learning and memory.


Method

Subjects

Thirty-eight male Lister Hooded rats were used as subjects. They were approximately 12 months old at the start of the study. The animals were housed in groups of four, with water constantly available in the home cage. The rats had a free-feeding body weight range of 460–600g, and were housed in groups of four, with water constantly available in the home cage. The rats were maintained at 85% of their free-feeding weight throughout the experiment. All animals were weighed every day, and they were separated from the group, and housed and fed individually, overnight, if their weight varied away from 85%.

Apparatus

Conditioning chambers

Training was conducted in four identical operant-conditioning chambers (Camden Instruments Ltd.), from which the levers had been withdrawn. The chambers were ventilated by a fan that also provided a 68-dB(A) background noise. The reinforcement, one 45-mg food pellet, was delivered to a food tray, which was covered by a clear, Perspex® hinged-flap. A micro-switch was operated when the flap was opened. A jeweled house-light was located on the center of the chamber ceiling (overhead light). Another light was located centrally on the chamber wall above the food tray (central light). Both lights were 2.8 W bulbs. Based on past studies (Reed et al., 1999), both stimuli were of equal salience.

Elevated plus maze

The EPM consisted of two open (35 cm × 12 cm) and two enclosed arms (35 cm × 12 cm × 40 cm) and a center square (12 cm × 12 cm). The maze was elevated 50 cm above the floor. Open arms were surrounded by a 0.5-cm ledge and the entire floor was covered in black rubber. A black surround was placed around the apparatus to minimize visual cues. A schematic representation of an EPM is shown in Fig. 1.

Schematic representation of an elevated-plus maze (from Augusta University http://www.augusta.edu/core/labs/sabc/elevatedplusmaze.php)

Procedure

Stimulus pre-exposure task

Phase 1 (pre-exposure) consisted of eight 30-min sessions. In each session, the subjects received ten 30-s non-reinforced exposures to a light (CSPE). For half of the subjects, the central light was used as the CSNPE, whilst the overhead light was used as the CSPE. For the other half, the central light was used as the CSPE, whilst the overhead light was used as the CSNPE. The first stimulus presentation occurred 150 s after the onset of the session. All subsequent inter-trial intervals were 150 s.

Phase 2 (conditioning) consisted of six 30-min sessions, during which all subjects received ten 30-s presentations of the CSPE, immediately followed by reinforcement. In addition, they received ten 30-s presentations of the stimulus CSNPE immediately followed by reinforcement. The presentation of the experimental events was counterbalanced using a random, computer-generated order. Responses were recorded as entries to the magazine flap. All the subjects received the same programmed events.

Elevated plus maze

On the day of testing, subjects were removed from their home cages and transported individually to the testing room. Each subject was placed in the center square facing an open arm, and was allowed to explore freely the apparatus for a period of 5 min. Each 5-min trial was videotaped, and later analyzed by a trained observer using specifically designed software (Mazetime, Oxford, UK). The analysis of rats’ behavior in the maze was undertaken “blind” to the rats’ performance after both behavioral tests were completed. The EPM was cleaned with a 20% ethanol solution between trials (Bulos, Pobbe, & Zangrossi, 2015).

A variety of behavioral measures were recorded that have been shown to selectively reflect anxiety and locomotor activity (Cruz, Frei, & Graeff, 1994 Pellow et al., 1985). Anxiety parameters are taken to be reflected in the rats’ preference for the closed sections of the maze as opposed to the open sections (Cruz et al., 1994 Pellow et al., 1985). These consist of: (a) the number of entries made by subjects into the open arms relative to overall arm entries (ratio of open-entries, ROE – i.e., number of open-arm entries/total arm-entries) and (b) the time spent by subjects on the open arms relative to overall trial duration (ratio of open-time, ROT – i.e., time spent in open-arms/overall trial duration [300 s]). Low values for these anxiety measures indicate higher anxiety, and higher values indicate lower anxiety (same preference for closed and open places). The number of entries made into closed arms relative to overall entries (ratio of closed-entries, RCE), and the time spent by subjects in the closed arms relative to overall trial duration (ratio of closed-time, RCT), were recorded as well. The locomotor measures consisted of the total number of entries into any of the maze arms (total-entries, TE), and the number of entries into the closed arms (closed-entries, CE). The subject’s location on the maze was defined as four paws being present in a maze arm. These estimate the overall activity of the rat rather than any preference for particular areas of the maze – and reflect the degree of activity of the rat independent of anxiety.


Introduction

If a stimulus is repeatedly presented without other consequence (`preexposure') and is later used as the conditioned stimulus (CS) in a Pavlovian conditioning paradigm, the prexposed (PE) CS develops a weaker association with the unconditioned stimulus (UCS) than does a non-preexposed (NPE) CS, as measured by the strength of the resulting conditioned response (CR). This difference in the strength of CRs elicited by PE and NPE CSs, respectively, is known as `latent inhibition' (LI) 19, 20. LI has been extensively studied in many species, including man, in part owing to the significance it has for a number of key issues in the psychology of animal learning and selective attention 19, 24, and because disruption of LI has been related to the cognitive abnormalities that characterise acute schizophrenia 6, 7, 8, 31. Given the conceptual importance that LI has achieved in these contexts, among others, the neural basis of the phenomenon is also now becoming a focus of great interest, in terms of both abstract modelling of the likely networks involved [24]and experimental studies of the brain systems that mediate it 8, 31. There is as yet, however, only a limited data base to guide these theoretical and experimental investigations, and controversy surrounds the identification of the key brain structures involved in LI 8, 18, 25, 31.

This line of study commenced with Solomon and Staton's report [25]that the abolition of LI observed after systemic administration of indirect dopamine (DA) agonists, such as amphetamine and nicotine [11], both now well replicated effects 8, 23, 29, 32, 33, could be produced also by direct application of amphetamine to the nucleus (n.) accumbens but not to the caudate-putamen. More indirect evidence consistent with the conclusion drawn by these workers—namely, that it is DA release specifically in n. accumbens which is reponsible for the blockade of LI—subsequently emerged from two sources. First, it became clear that LI is disrupted in the rat [32]by low, hyperactivity-inducing systemic doses of amphetamine that are considered to produce their effects primarily via the mesolimbic dopaminergic system, but not by high, stereotypy-producing doses, which act primarily via striatal DA mechanisms [14]. Such inverse dose-dependence of the effect of amphetamine on LI has also been reported in human subjects [9]. Second, it was shown that systemic nicotine, at doses that cause DA release in n. accumbens but not in the caudate-putamen 1, 10, is able to block LI consistent with the hypothesis that this effect is mediated by DA release, it was reversed by concomitant administration of the DA receptor antagonist, haloperidol [11].

The view that dopaminergic transmission in n. accumbens plays a key role in LI has, however, been challenged in a series of experiments from Trevor Robbins' laboratory in Cambridge 16, 17, 18. There are two main components to this challenge.

The first concerns the general role of dopaminergic transmission in LI. Killcross et al. 16, 17replicated the findings, made in a number of other laboratories (for references, see [8]), that DA releasing drugs (in their case, amphetamine) block, and DA receptor antagonists (in their case, α-flupenthixol) potentiate, LI. As in previous such experiments, furthermore, they were able to show, under certain conditions, that the observed changes in performance caused by these drugs were apparent only in the PE condition, NPE groups being largely unaffected by the drug treatments. However, they were then able to return LI to non-drug levels by altering the intensity of the UCSs (both aversive and appetitive, in two different paradigms) used in their experiments: decreasing UCS intensity restored LI (by weakening performance in the PE condition) under amphetamine, while increasing UCS intensity eliminated LI (by strengthening performance in the PE condition) under α-flupenthixol. The authors of these papers interpreted their results as indicating that altering overall dopaminergic transmission by systemic DA agonists or antagonists does not selectively affect the phenomenon of LI, as claimed, e.g. by Solomon and Staton [25], Gray et al. [6]and Weiner [31], but rather alters the effective capacity of the UCS to provide Pavlovian reinforcement. According to their argument, effective UCS intensity is increased by agonists and decreased by antagonists, the changes then appearing artefactually as altered LI (blocked or potentiated, respectively) because of an interaction between floor or ceiling effects and the resulting level of conditioning.

Gray et al. [8]have argued, however, that this potential artefact cannot account for the bulk of the relevant data. For example, the blockade of LI by systemic amphetamine is independent of the degree of overall conditioning (as measured by the level of conditioned suppression in placebo-treated NPE groups see Fig. 1 in [8], presenting data from I. Weiner et al., in preparation), although the Killcross position predicts that these phenomena should co-vary. Some of the results reported below are similarly incompatible with this position, as we shall see. It should be noted, however, that Killcross and Dickinson [15]have recently elaborated a more sophisticated version of their hypothesis, according to which the changes in effective UCS intensity putatively caused by DA agonists and antagonists affect, not the process of conditioning as such, but the degree of context shift between the preexposure and conditioning phases of the LI paradigm. Since the UCS is not present during preexposure, then if it is made functionally more intense (in virtue say of amphetamine administration) when it is present in the conditioning phase, this is the equivalent of a larger context shift, which is known to weaken LI 19, 24. Conversely, neuroleptics could in the same way reduce context shift, and so strengthen LI. The data presented here do not speak directly to this more sophisticated version of the Killcross hypothesis accordingly, in the remainder of this article we refer only to the straightforward UCS intensity hypothesis, not involving context shift.

In the second component to the challenge, Killcross and Robbins [18]were unable to affect LI by injections of amphetamine directly into n. accumbens, although the expected blockade of LI occurred when this compound was administered systemically. Given this failure to replicate Solomon and Staton's report [25]that intra-accumbens amphetamine did block LI, the second component of the Killcross et al. challenge is the claim that, whatever effects alteration of dopaminergic transmission has on LI, these are not mediated by dopaminergic terminals or synapses within n. accumbens. (As an alternative, Killcross and Robbins [18]propose that such effects are mediated by altered dopaminergic transmission within the caudate-putamen. For evidence against this hypothesis, see [8].)

Only further experiments aimed directly at testing the role in LI of n. accumbens dopaminergic transmission will succeed in resolving the issues that Killcross and Robbins [18]have raised. We and other colleagues reviewed some relevant findings in a paper presented at the 1993 Madrid meeting of the European Brain and Behaviour Society [8]. In the present paper, we briefly describe the results of several additional experiments (reported in full elsewhere). All the behavioural experiments used our three-stage conditioned suppression paradigm 5, 11. In this, after initial training to lick for water, on the first day a to-be-CS (usually a tone) is preexposed a number of times (with controls remaining an equivalent period of time in the experimental chambers, but without stimulation) on the second day, all animals receive two CS-UCS (footshock) Pavlovian pairings and on the fourth day, after a re-baseline day, the CS is presented to the animal while it is licking for water. Water is not available on the preexposure or conditioning days. If the number of preexposures is set at 30–40, robust LI is usually observed in controls, providing a baseline for attempts to abolish it with ten preexposures, controls do not normally show LI, providing a baseline for attempts to potentiate it. The effect of the CS is measured at test as the degree of suppression of the lick rate relative to the baseline rate prior to CS presentation LI consists in a lower level of conditioned suppression in PE relative to NPE subjects. The data are most often presented as a suppression ratio (that is, the ratio of the number of licks during CS presentation to the number of licks over an equivalent period of time prior to CS presentation 0=total suppression, 0.5=no suppression). Drugs are given either prior to the preexposure session, or prior to the conditioning session, or both, but not prior to the test session.


Psychology of Learning Ch. 12 book questions

b. Making a running wheel available during non-meal periods
c. Both a and b are correct.

b. She should eat several small meals per day.

c. Injection of an endorphin blocker

b. it occurs more readily in adolescent individuals and rats than older individuals and rats.
c. both rats and humans become quite uninterested in food.

b. excessive water drinking FT or FI
c. excessive eating VT or VI

b. tends to emerge during the post-reinforcement interval.

b. a well-known food item
c. a disliked food item

b. both undertake low levels of activity.
c. Both a and b are correct.

b. making a running wheel available during the periods between meals.
c. Both a and b are correct.

b. associative specificity
c. CS-US relevance

c. Both a and b are correct.

c. food conditioned response

b. a taste aversion to porridge.

b. form of self-punishment.
c. fixed action pattern.

b. Classical conditioning
c. Elicited behavior

b. ineffective only if the daughter used to like beans but somehow grew to dislike them.
c. relevant only if the daughter also receives a treat after eating the beans.

c. changing one's attitude about one's body image.

b. a very unusual, but trivial, food item prior to the chemotherapy session.
c. Both a and b are correct.

b. must occur immediately following food ingestion.
c. Both a and b are correct.


4. Discussion

4.1. Summary and validity of the findings

The goal of this study is to further characterize behavioral memory induced by pairing a tone with stimulation of the cholinergic nucleus basalis. This line of research was initiated by the discovery that tone paired with stimulation of the nucleus basalis induced CS-specific shifts of frequency receptive fields in the primary auditory cortex (Bakin & Weinberger, 1996). Subsequently, several laboratories replicated and extended this finding, all within a framework of cholinergic mechanisms underlying learning and memory (e.g., Chen & Yan, 2007 Kilgard & Merzenich, 1998 Moucha et al., 2005 Zhang, Hamilton, Nathanson, & Yan, 2006). Although extensive pharmacological studies had, and continue to, implicate the cholinergic system in learning and memory, they are limited in the ability to pinpoint specific cholinergic neural structures or circuits and to actually induce memory. Thus, such nucleus basalis stimulation studies are valuable in their ability to locate critical cholinergic loci. However, demonstrations of NB-induced specific plasticity provide a presumptive, rather than a direct, link between the cholinergic system and actual memory. Even granting that specific associative plasticity is at least part of a substrate of memory, a general tendency to more-or-less equate learning-related neural plasticity with memory can be considered to constitute a �tegory error”, i.e., attribution to a part the properties of the whole (Ryle, 1949). Thus, the rationale for determining if NB stimulation can induce behavioral memory, as opposed merely to inducing neural plasticity, is that allegations of cholinergic sufficiency for memory formation can be directly tested.

If activation of the NB during natural learning is sufficient to induce memory, as well as neural plasticity, then appropriately-timed direct stimulation of the NB should be sufficient to also induce memory. Moreover, NB-induced associative memory should have major characteristics of natural associative memory. Previous experiments had revealed that this type of memory is associative, highly specific, rapidly acquired, can be induced in a single session, becomes more precise over time (𠇌onsolidates”) and is retained for at least several days (Introduction see also Weinberger, 2007 Weinberger et al., in press). They also revealed that the NB-induced memory does require the engagement of muscarinic cholinergic receptors (Miasnikov et al., 2008b). The current study examined experimental extinction and the effects of CS and NBstm unpaired pre-exposure (i.e., potential effects of LI/LIRR, latent inhibition or learned irrelevance).

4.2. Extinction

It is now almost universally agreed that behavioral extinction indexes the learning of a new “inhibitory” contingency rather than the loss of the original association. Such inhibitory learning is itself both expressed by the reduction of response to the CS and by its ability to interfere with new learning to the CS (Bouton, 2007 Mackintosh, 1974). Thus, extinction is indicative of the flexibility of mnemonic processes in adjusting behavior to changing circumstances. The current findings show that after pairing a tone with stimulation of the NB in the IP group, which induces specific associative memory, disrupting the initial contingency produces a loss of frequency-specific response. We interpret this change in behavior as indexing experimental extinction as it encompasses the key elements of extinction, i.e., elimination of the contingency between the CS and NBstm. However, the procedures that we employed are different from standard extinction protocols, in which the US is simply absent while the CS continues to be presented. Instead of removing the NBstm, which is a proxy for the US, we retained the “US” but removed its ability to be predicted by the CS tone.

Our rationale was twofold. First, this permitted a balanced design with the IU group so that both groups experienced the same stimuli in both phases of the experiment, undergoing only a change in the CS–NBstm relationship. Second, and generally overlooked, is the fact that removal of the US also produces a change in the state of subjects. For example, removing a shock US in fear conditioning also reduces the arousal level of the animals. We wished to avoid this confound, not only because it complicates the interpretation of the results, but because it would lead to grossly different levels of ACh released into the cerebral cortex, including the auditory cortex. There is close relationship between arousal level and the level of ACh in the cortex, the greater the arousal, the greater the level of ACh (e.g., Cape & Jones, 1998, 2000 Celesia & Jasper, 1966 Metherate, Cox, & Ashe, 1992 Phillis, 1968 Phillis & Chong, 1965 Rasmusson & Szerb, 1976). Therefore, removing NBstm from the IP group during the second phase of the experiment would have had a detrimental consequence: subjects’ lowered arousal level would have meant that comparisons between the IP and IU groups during the second phase would engender a confound in arousal level, so that any differences in behavior could not be attributable exclusively to the training contingencies.

That the IP group exhibited behavioral extinction when its contingency was changed indicates that NB-induced memory possesses another important attribute of natural associative memory. This finding adds to the evidence that engagement of the NB during normal learning is sufficient to induce natural associative memory. That NB-induced memory possess attributes of natural memory is important because it reduces the possibility that induced memory is simply a demonstration of what the brain can be 𠇏orced to do” by an intervention such as electrical microstimulation. We do realize that in principle, one could examine all associative phenomena to determine if NB-induced memory has all of the attributes of normal associative memory. However, we believe that this would not be a good strategy, and address this issue in the final section of this paper.

4.3. Effect of pre-exposure to unpaired tone and NBstm

The IU group first received tone and NBstm in unpaired and later received them in a standard, paired relationship. This constitutes pre-exposure to both the CS and the “US”, i.e., NBstm which was presented at the time that a standard US ordinarily would be given. With reference to such “proxy” status, it is important to note that NBstm that induces specific associative memory is motivationally neutral, i.e., it has neither positive nor negative valence (Miasnikov et al., 2008a) although it can elicit changes in respiration and heart rate (McLin, Miasnikov, & Weinberger, 2002b). Thus, the current experiment is not merely a demonstration that brain stimulation which is appetitive or aversive can serve as a US, as it is often used in tracing a conditioning circuit (e.g., Chapman, Steinmetz, & Thompson, 1988 Cruikshank, Edeline, & Weinberger, 1992 Steinmetz, Lavond, & Thompson, 1989). Rather, it is a test of a particular model of natural sensory associative learning, which posits a 𠇏inal common path” for the long-term, specific storage of information via activation of the nucleus basalis, its release of ACh into the auditory cortex and the subsequent engagement of cholinergic receptors in the auditory cortex (Weinberger, 1998, 2007).

Pre-exposure to a CS generally retards subsequent acquisition to that stimulus, a process known as “latent inhibition” (e.g., Lubow & Moore, 1959). Less well known, but also established, are the effects of exposure to the US prior to attempting conditioning. This “US pre-exposure effect” also is indexed by retardation of acquisition, when the US is later used in conditioning (Kremer, 1971).

Additionally, retardation of learning when there is pre-exposure to both the CS and US has been interpreted as “learned irrelevance” (LIRR). (e.g., Baker, 1976 Baker & Mackintosh, 1977 Bennett, Maldonado, & Mackintosh, 1995). However, LIRR has been disputed other workers have been arguing that the CS/US pre-exposure effect can be explained by recourse to the sum of latent inhibition and the “US alone pre-exposure effect” (e.g., Bonardi & Hall, 1996 Bonardi, Hall, & Ong, 2005 Bonardi & Ong, 2003). Regardless of the ultimate theoretical explanation of the effects of CS and US unpaired pre-exposure on later associative learning, the role of the NB is of interest, at the very least with reference to the characteristics of natural associative memory. If the pre-exposure effect were found with CS/NBstm pre-exposure, then there might be a neural link between a specific brain structure and several important psychological problems.

Group IU received about 200 presentations each of tone and NBstm (i.e., CS and “US”) alone prior to their pairing when the contingencies were reversed in the second phase of the experiment, thus potentially producing LI/LIRR due to pre-exposure to the CS, the “US” or both.

The present study does provide modest support for the pre-exposure effect using tone and NB stimulation. First, the magnitude of CS band conditioned responses was smaller in the IU group than in the IP group, specifically 42% of the latter group ( Fig. 3 ). However, this effect was not statistically significant, therefore it should not be given undue weight. Second, the S–T analysis of response latencies ( Fig. 5 ) demonstrates that the pre-exposure to unpaired stimulation eliminated the early components of conditioned responses following subsequent pairing, delaying associative behavior several seconds (e.g., Fig. 4C and F ). The early component is ordinarily well-developed following training in naïve subjects Fig. 4B and E ). In addition, the pre-exposure retardation of acquisition was specific to the CS band, a degree of specificity that has not been reported previously. However, whether the current effects are due to latent inhibition or learned irrelevance cannot be determined from the present study.

4.4. Spectro-temporal patterns of associative responses

As noted, CS-specific associative memory developed both in the IP group in initial training and in the IU group after contingency reversal. However, spectro-temporal analyses of associative responses revealed a different latency of associative responses. This associative latency effect would not have been detected had analysis been limited to the 2-s period of tone presentation. Rather, it might have been concluded that pre-exposure of the IU group to the CS and NBstm unpaired had produced little associative response.

These findings demonstrate in general the importance of employing behavioral analyses that are sufficiently sensitive to avoid a Type II error. Thus, while such pre-exposure did not appear to retard subsequent acquisition of processing of frequency information, the significant increase in response latency may indicate the involvement of additional processing resources. Thus, the IU group may have had to overcome presumptive prior learning that the CS predicted nothing, so that suppression of this knowledge may have required an extra step before the new association could become manifest. Such “on-line” behavioral tracking could prove useful in pursuing networks of neurons engaged in the formation of specific memories.

4.5. Future directions for NB-induced associative memory

The current study has demonstrated that specific, associative behavioral memory that is induced by stimulation of the nucleus basalis exhibits experimental extinction. However, it is moot regarding latent inhibition, probably because of the use of physiologically-potent NBstm, which is neither sensory nor motivational in character. These findings raise the issue of how many characteristics of natural memory should be found to also occur for NB-induced memory? For example, should latent inhibition be re-studied by presenting tone alone before pairing it with NBstm? We have explained above our rationale for the current design of maintaining the same overall density of tone and NBstm throughout the study. Innumerable other associative phenomena could be studied as well (Bouton, 2007). At what point is the specter of 𠇍iminishing returns” attained? We suggest that this point may now have been reached. NB-induced memory has been shown to possess key attributes of natural associative memory: associativity, specificity, rapid acquisition, consolidation, long-term (days) retention and now experimental extinction.

NB-induced memory also permits a 𠇍issection” of memory processes. It does not involve motivational and emotional processes thus, aspects of “pure” associative processes can be studied neurobiologically. For example, now that NB-induced memory has been shown to be very similar to natural memory, it would be appropriate to determine the neural effects and the neural networks that enable NBstm to produce associative memory. Another advantage of NB-induced memory is that it provides a way to understand the contents of memory, because the level of activation controls the level of detail that is encoded, stored and retrieved low levels of activation produces association without frequency specificity (𠇏lat” generalization gradients), whereas moderate levels of activation produce both associativity and specificity (“sharp” generalization gradients with a peak at the CS frequency band) (Weinberger et al., 2006).

Finally, a third line of inquiry that is now possible given the known attributes of NB-induced memory is that of investigating the behavioral use of the embedded information. For example, suppose a subject has “learned” that an 8.0 kHz tone is important because it has been paired with NBstm, although the tone likely signifies importance without serving as a signal for anything. Nonetheless, if 8.0 kHz is now behaviorally pre-potent, then the subject should be more likely to pay attention when it encounters this stimulus in a new setting, in the absence of NBstm. The heightened salience of this tone should have predictable consequences if indeed NB-induced memory involves the encoding of information in the same sense that natural learning does, e.g., the importance of the CS frequency. This information should be capable of facilitating new learning or the solution of a completely novel problem. This outcome would serve as the first validation that specific information can be directly “inserted” into the brain.


Latent inhibition mediates N1 attenuation to repeating sounds

This work was supported by NIBIB grant EB002011 to Gabriele Gratton and a G. Ellsworth Huggins Graduate Scholarship from the University of Missouri–Columbia Graduate School to Jeffrey J. Sable. The authors wish to thank Nelson Cowan for his input on this work.

Abstract

Sound repetition typically reduces auditory N1 amplitudes, more so at higher rates. This has been attributed to refractoriness of N1 generators. However, evidence that N1 attenuation is delayed 300–400 ms after the first occurrence of a repeated sound suggests an alternative process, such as inhibition, that requires 300–400 ms to become fully operational. We examined the N1 to trains of fixed-interval (100, 200, 300, 400 ms) tones for evidence of effects predicted by models of refractoriness and of latent inhibition. Regardless of interval, latency of the eliciting tone from train onset determined N1 amplitudes during the first 400 ms of the train, which decreased in this window. The results show that N1 attenuation cannot be due simply to refractoriness, which would elicit the smallest N1 to the second tone. An inhibitory neural circuit can account for these and previous results, and may be important to auditory perceptual processing.


Results

Latent Profile Analyses in the Community Sample

Model fit for solutions with 2𠄶 latent classes were examined (see Table 1). The Lo–Mendell–Rubin-adjusted LRT indicated that models with 2, 4, and 6 classes showed improved fit over those with one fewer class. Of these, the six-class solution was rejected because the best log-likelihood value was not replicated and two of the classes contained less than 5% of the sample. The four-class solution was ultimately selected as the best fitting model because it showed better discrimination among the classes (higher entropy value at 0.68) and a lower BIC value (2434.78) than the two-class solution. Individuals were then classified according to their most likely class membership. As illustrated in Supplementary Figure 1, the first class was characterized by low ratings on both Avoidance and Approach scales (class 1 [Low/Low] 24% of the sample), the second class was characterized by average Avoidance and average Approach ratings (class 2 [Average] 48% of the sample), the third class was marked by high ratings on Avoidance and average Approach (class 3 [High Avoid] 20% of the sample), and the fourth class reflected low ratings for Avoidance and high ratings for Approach (class 4 [High App] 8% of the sample).

Table 1. Model fit of the latent profile analysis in a community sample.

To explore the external correlates of these affective profiles, we examined how they differed on measures of motivation, distress tolerance, borderline personality features, mood and anxiety symptoms, and alcohol/drug use problems. Results of these analyses are presented in Table 2 and Figure 1. Probability of membership in the class characterized by low ratings on both of the RISQ affect scales (Low/Low) was associated with greater resilience to distress, lower mood and anxiety symptoms, fewer borderline personality features, and less behavioral inhibition and activation than membership in the other classes. Probability of membership in the class marked by distinctly high ratings on RISQ Avoidance motivation (High Avoid), in contrast, was associated with significantly lower distress tolerance than membership in the other three classes. Furthermore, membership in the High Avoid class was related to higher ratings of behavioral inhibition, mood and anxiety symptoms, borderline personality features, and alcohol/drug use than membership in the classes with low ratings on RISQ Avoidance (classes 1 and 4). In contrast, the probability of membership in the class characterized by high ratings selectively on RISQ Approach motivation (High Approach) was associated with greater behavioral activation (BAS) and lower anhedonic depression symptoms than the probability of membership in the classes marked by low to average ratings on RISQ Approach motivation (classes 1 and 2).

Table 2. External correlates of RISQ affective profiles in a community sample.

Figure 1. Probability of class membership correlations with external variables by RISQ affective profiles in a community sample.

Predictive Affect Profiles in the Prison Sample

Using the latent profile structure extracted from the community sample, we applied the four-class solution to the prison sample. Class 1 (Low/Low) characterized 30% of the sample, class 2 (Average) characterized 47% of the sample, class 3 (High Avoid) characterized 16% of the sample, and class 4 (High App) characterized 7% of the sample.

In terms of substance use, the probability of membership in the class marked by selectively high ratings on RISQ Avoidance (class 3) was associated with higher prior alcohol use symptoms and cannabis use symptoms than the classes characterized by low and average scores on the RISQ affect scales (classes 1 and 2, respectively). Next, in terms of criminal activity, probability of membership in the High Approach class was associated with higher total number of crimes and non-violent crimes than membership in the other classes. Probability of membership in the class marked by low ratings on both of the RISQ affect scales (class 1) was associated with higher total number of violent crimes than membership in class 2 or 3, though this relationship was largely driven by higher numbers of sex crimes in class 1. Finally, in terms of disciplinary violations within prison, the probability of membership in the High Approach class was associated with higher total number of disciplinary violations than membership in class 2. Probability of membership in the High Avoid class was associated with higher number of violations against persons than membership in class 2 but lower number of substance use violations than membership in classes with low and average ratings on the RISQ affect scales (classes 1 and 2). Further, probability of class membership in the Average class was associated with fewer total days in segregation as punishment for substance use violations than membership in classes marked by high avoid and approach, respectively (classes 3 and 4) (see Table 3 and Figure 2).

Table 3. External correlates of RISQ affective profiles in a prison sample.

Figure 2. Probability of class membership correlations with external variables by RISQ affective profiles in a prison sample.


Results

Experiment 1: AMPA/nAChR interaction in latent inhibition

To examine the roles of nAChRs and AMPARs in latent inhibition of cued fear conditioning, mecamylamine alone, NBQX alone, or mecamylamine and NBQX together were given prior to pre-exposure to the CS (i.e., latent inhibition). It was expected that mecamylamine would not block latent inhibition, based on previous results (Gould et al. 2001). In addition, it was expected that NBQX would not alter latent inhibition based on a preliminary study (Gould and Lewis 2003) and based on results from an experiment that examined the effects of NBQX on fear conditioning (Lu and Wehner 1997). However, if nAChRs and AMPARs are mediating similar processes involved in latent inhibition, coadministration of the two drugs should abolish latent inhibition. A one-way analysis of variance revealed an overall effect of drug [F(4,37) = 11.04, P < 0.001]. Post-hoc analysis revealed significant differences between saline pre-exposed and saline non-pre-exposed groups (P < 0.05), with pre-exposed mice having higher suppression ratios compared with non-pre-exposed mice. This indicates the establishment of latent inhibition ( Fig. 1 ). If mecamylamine has no effect on latent inhibition, we would then expect this group to have suppression ratios that are significantly higher than saline non-pre-exposed mice and similar to saline pre-exposed mice. There were significant differences between mecamylamine pre-exposed and saline non-pre-exposed groups (P < 0.05), but no differences were observed between the mecamylamine pre-exposed mice and the saline pre-exposed mice (P > 0.05), suggesting that nAChRs antagonism alone does not block the establishment of latent inhibition ( Fig. 1 ). This result is consistent with a previous finding (Gould et al. 2001). Similarly, if NBQX has no effect on latent inhibition, we would then expect that the group-administered NBQX would have suppression ratios that are significantly higher than saline non-pre-exposed mice, but similar to saline pre-exposed mice. There were significant differences between NBQX pre-exposed and saline non-pre-exposed mice (P < 0.05), and no differences were observed between saline pre-exposed mice and NBQX treated pre-exposed mice (P > 0.05). This data suggests that AMPAR antagonism alone does not disrupt latent inhibition ( Fig. 1 ).

The effects of NBQX (30.0 mg/kg AMPAR antagonist), mecamylamine (1.0 mg/kg nAChR antagonist), or coadministration of the two drugs on latent inhibition of cued fear conditioning. There were significant differences between saline pre-exposed (Sal Pre) and saline non-pre-exposed (Sal No Pre) mice, indicating that latent inhibition was established. Neither NBQX (NBQX Pre) nor mecamylamine (Mec Pre) administered alone on pre-exposure day had any effect on latent inhibition. The coadministration of NBQX and mecamylamine on pre-exposure day (NBQX /Mec Pre) blocked latent inhibition of cued fear conditioning. Light gray bars represent pre-exposed groups. Dark gray bars represent non-pre-exposed groups. Error bars, ± SEM. ( * ) Significantly different from saline pre-exposed mice.

To examine the possibility that coantagonism of nAChRs or AMPARs could disrupt latent inhibition, mecamylamine and NBQX were coadministered prior to pre-exposure. If coantagonism of these two receptors blocks latent inhibition, we would then expect the suppression ratios for this group to be significantly lower than saline pre-exposed mice and similar to saline non-pre-exposed mice. Post-hoc analysis revealed significant differences between the mecamylamine/NBQX pre-exposed and saline pre-exposed groups (P < 0.05) and no differences were observed between the coadministration group and saline non-pre-exposed group (P > 0.05), indicating that the coantagonism of these receptors blocked the establishment of latent inhibition ( Fig. 1 ). The time to initiate the first lick of the testing trial was measured and compared between groups. A one-way ANOVA revealed no differences in lick latencies for any groups [F(4,37) = 0.802, P > 0.05]. Thus, drug conditions and preexposure conditions did not disrupt initiation of licking on testing day.

To examine the possibility that the lack of effect observed in both the NBQX pre-exposed and mecamylamine pre-exposed groups could have resulted from lasting effects of either drug administered on pre-exposure day that carried over to training day, NBQX or mecamylamine was administered to non-pre-exposed mice and compared with saline non-pre-exposed mice. A one-way ANOVA revealed no differences between saline non-pre-exposed mice and either NBQX or mecamylamine non-pre-exposed mice [F(2,21) = 1.297, P > 0.05], suggesting that neither NBQX nor mecamylamine had lasting effects on training day (data not shown).

Experiment 2: NMDA/nAChR interactions in latent inhibition

Activation of nAChRs can depolarize neurons (Roerig et al. 1997 Hefft et al. 1999) and also activate cell-signaling cascades by mediating calcium influx (Chang and Berg 2001 Nakayama et al. 2001 Berg and Conroy 2002 Dajas-Bailador et al. 2002b Utsugisawa et al. 2002 Brunzell et al. 2003). This ability of nAChRs to activate cell-signaling cascades similar to NMDARs suggests that nAChRs could interact with or perform a similar function to NMDARs during learning. To test whether nAChRs and NMDARs mediate similar processes, a dose of MK-801 subthreshold for disrupting fear conditioning (0.05 mg/kg, dose based on dose-response experiment) either alone or in combination with mecamylamine (1.0 mg/kg) was administered. A one-way ANOVA revealed an overall effect of treatment condition [F(3,36) = 9.20, P < 0.05]. Post-hoc analysis revealed significant differences between saline pre-exposed and saline non-pre-exposed (P < 0.05) mice, indicating latent inhibition was established ( Fig. 2 ). MK-801 pre-exposed mice were not significantly different from saline pre-exposed mice (P > 0.05) and were significantly different from non-pre-exposed mice (P < 0.05). These data suggest that this dose of MK-801 was ineffective at disrupting latent inhibition ( Fig. 2 ). If the coadministration of MK-801 and mecamylamine disrupts latent inhibition, we would then expect these mice to demonstrate suppression ratios similar to saline non-pre-exposed mice and significantly different from saline pre-exposed mice. Post-hoc analysis revealed that the group that received both antagonists demonstrated suppression ratios that were not different form saline non-pre-exposed mice (P > 0.05) and were significantly lower than saline pre-exposed mice (P < 0.05), demonstrating that the coadministration of MK-801 and mecamylamine disrupted latent inhibition of cued fear conditioning ( Fig. 2 ). There was a significant effect of drug on latency to first lick [F(3,36) = 5.89, P < 0.05]. The MK-801 pre-exposed mice demonstrated longer latency to initiate the first lick on testing day (P < 0.05 for all comparisons). However, these mice demonstrated suppression ratios similar to saline pre-exposed mice, suggesting that this difference had little effect on the resulting suppression ratios on testing day.

The effects of MK-801 (0.05 mg/kg NMDAR antagonist), mecamylamine (1.0 mg/kg nAChR antagonist), or coadministration of the two drugs on latent inhibition of cued fear conditioning. There were significant differences between saline pre-exposed (Sal Pre) and saline non-pre-exposed (Sal No Pre) mice, indicating that latent inhibition was established. The coadministration of MK-801 and mecamylamine on pre-exposure day (MK/Mec Pre) blocked latent inhibition of cued fear conditioning. Light gray bars represent pre-exposed groups. Dark gray bars represent non-pre-exposed groups. Error bars, ±SEM. ( * ) Significantly different from saline pre-exposed mice.

Experiment 3: AMPA/nAChR interaction in fear conditioning

To examine the role of nAChRs and AMPARs in fear conditioning, mecamylamine alone, NBQX alone, or both drugs together were administered prior to training. It was expected that neither mecamylamine nor NBQX would block cued or contextual fear conditioning (Lu and Wehner 1997 Gould and Wehner 1999b), but coadministration of the two drugs would block contextual fear conditioning if AMPARs and nAChRs mediate similar processes involved in contextual conditioning. A one-way analysis of variance examining baseline freezing on training day revealed no differences between groups [F(5,41) = 0.51, P > 0.05] ( Fig. 3 ). A one-way analysis of variance performed on freezing to the context on testing day revealed an overall effect of drug [F(5,41) = 5.01, P < 0.01]. Post-hoc analysis revealed significant differences between the saline group and both of the mecamylamine and NBQX coadministration groups for contextual conditioning (P < 0.05 for both groups) ( Fig. 3 ).

The effects of NBQX (15.0 and 30.0 mg/kg), mecamylamine (1.0 mg/kg), or the coadministration of the two drugs on contextual fear conditioning. There were no differences in baseline freezing on training day for any of the groups. Neither NBQX nor mecamylamine administered alone had any effect on contextual fear conditioning on testing day when compared with saline controls. However, the coadministration of 1.0 mg/kg mecamylamine with 15.0 mg/kg or 30 mg/kg NBQX on training day significantly reduced contextual fear conditioning on testing day compared with saline controls, and to mice administered either drug administered alone. Error bars, ±SEM. ( * ) Significantly different from saline, NBQX 15mg/kg, NBQX 30 mg/kg, and Mecamylamine.

In addition to examining changes in contextual conditioning, changes in cued fear conditioning were also examined. A one-way analysis of variance performed on pre-CS freezing scores revealed no significant differences between groups [F(5,41) = 2.32, P > 0.05], suggesting no differences in generalized freezing. A one-way analysis of variance performed on freezing during the CS revealed no significant differences between groups [F(5,41) = 1.99, P > 0.05] ( Fig. 4 ) suggesting that mice coadministered mecamylamine and NBQX can process the CS and form a CS association with the footshock US.

The effects of NBQX (15.0 mg/kg and 30.0 mg/kg), mecamylamine (1.0 mg/kg), or the coadministration of both drugs on cued fear conditioning. There was no difference in pre-CS freezing between groups, and there was no significant effect of drug on freezing to the CS on testing day. Error bars, ±SEM.

To examine the possibility that freezing to the CS in the NBQX/Mec group was a result of nonassociative processes, mice received either saline or coadministration of mecamylamine and NBQX, and then received two presentations of the CS without the US. It was expected that these mice would not show fear to the context nor to the CS during subsequent tests. There were no differences between baseline freezing [F(1,6) = 0.273, P > 0.05], freezing to the context [F(1,6) = 0.429, P > 0.05], or freezing to the CS [F(1,6) = 0.097, P > 0.05] between groups (data not shown). These data suggest that freezing to the CS on testing day observed in mice coadministered mecamylamine and NBQX and trained in fear conditioning with CS–US pairings reflected the formation of a CS–US association.

Experiment 4: NMDA/nAChR interactions in fear conditioning

To further test whether nAChRs and NMDARs mediate similar processes during learning, we administered a subthreshold dose of MK-801 (0.05 mg/kg) either alone or in combination with mecamylamine (1.0 mg/kg). A one-way analysis of variance examining baseline freezing on training day revealed no differences between groups [F(3,36) = 0.22, P > 0.05] ( Fig. 5 ). A one-way analysis of variance performed on freezing to the context on testing day revealed an overall effect of drug [F(3,36) = 21.72, P < 0.01]. Post-hoc analysis revealed significant differences between the saline group and the MK-801/mecamylamine coadministration group (P < 0.05). No differences were observed between the saline and MK-801 alone groups, demonstrating that this dose of MK-801 was subthreshold for disrupting contextual fear conditioning. These results suggest that nAChRs may mediate similar processes as NMDARs during contextual fear conditioning.

The effects of MK-801 (0.05 mg/kg), or the coadministration (at either training day only or both training and testing) of MK-801 and mecamylamine (1.0 mg/kg) on contextual fear conditioning. There were no differences in baseline freezing on training day for any of the groups. MK-801 administered alone had no effect on contextual fear conditioning compared with saline controls. However, the coadministration of 1.0 mg/kg mecamylamine with 0.05 mg/kg MK-801 on training day, or on both training day and testing day, significantly reduced contextual fear conditioning on testing day compared with saline controls. Error bars, ±SEM. ( * ) Significantly different from saline.

To ensure that the deficits in contextual fear conditioning did not result from state-dependent effects, MK-801 and mecamylamine were also coadministered on both training and testing days. Post-hoc analysis revealed a significant difference in freezing to the context between the saline group and group that received MK-801 and mecamylamine at both training and testing groups (P < 0.05). There was no difference in contextual fear conditioning between mice that received MK-801 and mecamylamine only at training and mice that received MK-801and mecamylamine at both training and testing. Thus, no state-dependent effects were seen.

In addition to examining changes in contextual conditioning, changes in cued fear conditioning were also examined. A one-way analysis of variance performed on pre-CS freezing scores revealed no significant differences between groups [F(3,36) = 0.88, P > 0.05], suggesting no differences in generalized freezing. A one-way analysis of variance performed on freezing during the CS revealed a significant effect of drug [F(3,36) = 10.42, P < 0.05] ( Fig. 6 ). Post-hoc analysis revealed that the saline group did not differ from either the MK-801 group or the MK-801/mecamylamine coadministration group. However, the MK-801/mecamylamine training/testing group showed significantly less fear to the CS than the saline group.

The effects of MK-801 (0.05 mg/kg), or the coadministration (at either training day only or both training and testing) of MK-801 and mecamylamine (1.0 mg/kg) on cued fear conditioning. There was no difference in pre-CS freezing between groups, but there was a significant effect of drug on freezing to the CS on testing day. The effect was due to reduced freezing in the group that received MK-801 and mecamylamine at both training and testing. Error bars, ±SEM. ( * ) Significantly different from saline.


Results

Participants

No significant group differences were obtained for age, t(38) = 0.306, p = 0.761, intelligence, t(38) = 𢄠.973, p = 0.337, alcohol consumption, t(38) = 0.478, p = 0.521, or cannabis consumption, t(38) = 0.169, p = 1.00. Table 1 shows drug-use profiles for the two groups.

Stop-Signal Task

Analyses of mean RT to go signals showed that khat users (536 ms) tended to respond more slowly than khat-free controls (474 ms), but this difference was not significant, p > 0.055. The percentage of choice errors to go-signals was low and did not discriminate between khat users (1.8%) and khat-free users (1.0%, p > 0.30). SSRTs were computed for each participant and for each group separately. All participants were able to stop their responses successfully in about half of the stop trials (51.9% in khat users and 49.7% in khat-free controls), indicating that the dynamic tracking algorithm worked well in both groups. Most importantly, SSRTs were significantly longer for users (236 ms) than for non-users (192 ms), F(1,38) = 33.21, p < 0.001, MSE = 584.624, η 2 p = 0.47, see Figure 2. The group effect remained largely significant even after using RT to go signals as covariate, F(1,38) = 29.97, p < 0.001, MSE = 599.701, η 2 p = 0.44. To test whether the magnitude of cognitive impairments is proportional to the amount of khat consumed, we computed Pearson correlation coefficients between the individual lifetime khat exposure, hours chewing and number of bundles used in a khat session, and SSRT. No significant correlations were obtained, probably due to very little between-subject variability.

Figure 2. Mean SSRT (stopping latency) as a function of Group (khat-free controls vs. khat users). Vertical capped lines atop bars indicate standard error of the mean.


Psychology of Learning Ch. 12 book questions

b. Making a running wheel available during non-meal periods
c. Both a and b are correct.

b. She should eat several small meals per day.

c. Injection of an endorphin blocker

b. it occurs more readily in adolescent individuals and rats than older individuals and rats.
c. both rats and humans become quite uninterested in food.

b. excessive water drinking FT or FI
c. excessive eating VT or VI

b. tends to emerge during the post-reinforcement interval.

b. a well-known food item
c. a disliked food item

b. both undertake low levels of activity.
c. Both a and b are correct.

b. making a running wheel available during the periods between meals.
c. Both a and b are correct.

b. associative specificity
c. CS-US relevance

c. Both a and b are correct.

c. food conditioned response

b. a taste aversion to porridge.

b. form of self-punishment.
c. fixed action pattern.

b. Classical conditioning
c. Elicited behavior

b. ineffective only if the daughter used to like beans but somehow grew to dislike them.
c. relevant only if the daughter also receives a treat after eating the beans.

c. changing one's attitude about one's body image.

b. a very unusual, but trivial, food item prior to the chemotherapy session.
c. Both a and b are correct.

b. must occur immediately following food ingestion.
c. Both a and b are correct.


Introduction

If a stimulus is repeatedly presented without other consequence (`preexposure') and is later used as the conditioned stimulus (CS) in a Pavlovian conditioning paradigm, the prexposed (PE) CS develops a weaker association with the unconditioned stimulus (UCS) than does a non-preexposed (NPE) CS, as measured by the strength of the resulting conditioned response (CR). This difference in the strength of CRs elicited by PE and NPE CSs, respectively, is known as `latent inhibition' (LI) 19, 20. LI has been extensively studied in many species, including man, in part owing to the significance it has for a number of key issues in the psychology of animal learning and selective attention 19, 24, and because disruption of LI has been related to the cognitive abnormalities that characterise acute schizophrenia 6, 7, 8, 31. Given the conceptual importance that LI has achieved in these contexts, among others, the neural basis of the phenomenon is also now becoming a focus of great interest, in terms of both abstract modelling of the likely networks involved [24]and experimental studies of the brain systems that mediate it 8, 31. There is as yet, however, only a limited data base to guide these theoretical and experimental investigations, and controversy surrounds the identification of the key brain structures involved in LI 8, 18, 25, 31.

This line of study commenced with Solomon and Staton's report [25]that the abolition of LI observed after systemic administration of indirect dopamine (DA) agonists, such as amphetamine and nicotine [11], both now well replicated effects 8, 23, 29, 32, 33, could be produced also by direct application of amphetamine to the nucleus (n.) accumbens but not to the caudate-putamen. More indirect evidence consistent with the conclusion drawn by these workers—namely, that it is DA release specifically in n. accumbens which is reponsible for the blockade of LI—subsequently emerged from two sources. First, it became clear that LI is disrupted in the rat [32]by low, hyperactivity-inducing systemic doses of amphetamine that are considered to produce their effects primarily via the mesolimbic dopaminergic system, but not by high, stereotypy-producing doses, which act primarily via striatal DA mechanisms [14]. Such inverse dose-dependence of the effect of amphetamine on LI has also been reported in human subjects [9]. Second, it was shown that systemic nicotine, at doses that cause DA release in n. accumbens but not in the caudate-putamen 1, 10, is able to block LI consistent with the hypothesis that this effect is mediated by DA release, it was reversed by concomitant administration of the DA receptor antagonist, haloperidol [11].

The view that dopaminergic transmission in n. accumbens plays a key role in LI has, however, been challenged in a series of experiments from Trevor Robbins' laboratory in Cambridge 16, 17, 18. There are two main components to this challenge.

The first concerns the general role of dopaminergic transmission in LI. Killcross et al. 16, 17replicated the findings, made in a number of other laboratories (for references, see [8]), that DA releasing drugs (in their case, amphetamine) block, and DA receptor antagonists (in their case, α-flupenthixol) potentiate, LI. As in previous such experiments, furthermore, they were able to show, under certain conditions, that the observed changes in performance caused by these drugs were apparent only in the PE condition, NPE groups being largely unaffected by the drug treatments. However, they were then able to return LI to non-drug levels by altering the intensity of the UCSs (both aversive and appetitive, in two different paradigms) used in their experiments: decreasing UCS intensity restored LI (by weakening performance in the PE condition) under amphetamine, while increasing UCS intensity eliminated LI (by strengthening performance in the PE condition) under α-flupenthixol. The authors of these papers interpreted their results as indicating that altering overall dopaminergic transmission by systemic DA agonists or antagonists does not selectively affect the phenomenon of LI, as claimed, e.g. by Solomon and Staton [25], Gray et al. [6]and Weiner [31], but rather alters the effective capacity of the UCS to provide Pavlovian reinforcement. According to their argument, effective UCS intensity is increased by agonists and decreased by antagonists, the changes then appearing artefactually as altered LI (blocked or potentiated, respectively) because of an interaction between floor or ceiling effects and the resulting level of conditioning.

Gray et al. [8]have argued, however, that this potential artefact cannot account for the bulk of the relevant data. For example, the blockade of LI by systemic amphetamine is independent of the degree of overall conditioning (as measured by the level of conditioned suppression in placebo-treated NPE groups see Fig. 1 in [8], presenting data from I. Weiner et al., in preparation), although the Killcross position predicts that these phenomena should co-vary. Some of the results reported below are similarly incompatible with this position, as we shall see. It should be noted, however, that Killcross and Dickinson [15]have recently elaborated a more sophisticated version of their hypothesis, according to which the changes in effective UCS intensity putatively caused by DA agonists and antagonists affect, not the process of conditioning as such, but the degree of context shift between the preexposure and conditioning phases of the LI paradigm. Since the UCS is not present during preexposure, then if it is made functionally more intense (in virtue say of amphetamine administration) when it is present in the conditioning phase, this is the equivalent of a larger context shift, which is known to weaken LI 19, 24. Conversely, neuroleptics could in the same way reduce context shift, and so strengthen LI. The data presented here do not speak directly to this more sophisticated version of the Killcross hypothesis accordingly, in the remainder of this article we refer only to the straightforward UCS intensity hypothesis, not involving context shift.

In the second component to the challenge, Killcross and Robbins [18]were unable to affect LI by injections of amphetamine directly into n. accumbens, although the expected blockade of LI occurred when this compound was administered systemically. Given this failure to replicate Solomon and Staton's report [25]that intra-accumbens amphetamine did block LI, the second component of the Killcross et al. challenge is the claim that, whatever effects alteration of dopaminergic transmission has on LI, these are not mediated by dopaminergic terminals or synapses within n. accumbens. (As an alternative, Killcross and Robbins [18]propose that such effects are mediated by altered dopaminergic transmission within the caudate-putamen. For evidence against this hypothesis, see [8].)

Only further experiments aimed directly at testing the role in LI of n. accumbens dopaminergic transmission will succeed in resolving the issues that Killcross and Robbins [18]have raised. We and other colleagues reviewed some relevant findings in a paper presented at the 1993 Madrid meeting of the European Brain and Behaviour Society [8]. In the present paper, we briefly describe the results of several additional experiments (reported in full elsewhere). All the behavioural experiments used our three-stage conditioned suppression paradigm 5, 11. In this, after initial training to lick for water, on the first day a to-be-CS (usually a tone) is preexposed a number of times (with controls remaining an equivalent period of time in the experimental chambers, but without stimulation) on the second day, all animals receive two CS-UCS (footshock) Pavlovian pairings and on the fourth day, after a re-baseline day, the CS is presented to the animal while it is licking for water. Water is not available on the preexposure or conditioning days. If the number of preexposures is set at 30–40, robust LI is usually observed in controls, providing a baseline for attempts to abolish it with ten preexposures, controls do not normally show LI, providing a baseline for attempts to potentiate it. The effect of the CS is measured at test as the degree of suppression of the lick rate relative to the baseline rate prior to CS presentation LI consists in a lower level of conditioned suppression in PE relative to NPE subjects. The data are most often presented as a suppression ratio (that is, the ratio of the number of licks during CS presentation to the number of licks over an equivalent period of time prior to CS presentation 0=total suppression, 0.5=no suppression). Drugs are given either prior to the preexposure session, or prior to the conditioning session, or both, but not prior to the test session.


Brain Research in Addiction

Samantha J. Brooks , . Dan J. Stein , in Progress in Brain Research , 2017

1.1 Broad Definitions of Impulsivity/Compulsivity

Previously, impulsivity and compulsivity were regarded as dissociable states underpinned by distinct neural mechanisms within the fronto-striatal network for sensation/risk seeking and aversion avoidance, respectively ( Dalley et al., 2011 Fineberg et al., 2014 ). However, neurobiological research since the advent of neuroimaging, has led to updated conceptualizations of impulsivity and compulsivity that broadly share common substrates within the fronto-striatal circuitry for high levels of automaticity, impaired cognitive inhibition , lack of self-control, and maladaptive self-regulation. Discrete differences in regional activation within this broad network may shed further light on the neural mechanisms of interaction between impulsivity and compulsivity that present as fluctuating symptoms for many mental disorders. For example, in SUD there appears to be a change from controlled drug use to habitual compulsivity over time (particularly in those with trait susceptibility for impulsivity), which is linked to Pavlovian-Instrumental Transfer (PIT) and a switch from ventral to dorsal striatum activation ( Brewer and Potenza, 2008 Everitt and Robbins, 2016 Robbins et al., 2012 ). Furthermore, fluctuations in impulsive and compulsive symptoms can occur within the individual that underpin comorbidity with other related psychiatric diagnoses (e.g., ADHD and OCRD), which also suggests variations in neuropathology across common brain circuits such as the fronto-striatal network, and possibly differences in genetic elements (e.g., single-nucleotide polymorphisms [SNP] and epigenetic effects). Therefore, it is pertinent to consider definitions of impulsivity and compulsivity that provides separate conceptualizations and whether interaction between them can be largely regarded as state (a behavior present only in certain contexts) or trait (a predisposition).


LONG-TERM DEPRESSION IN THE CEREBELLUM, HIPPOCAMPUS, AND NEOCORTEX

Long-term depression (LTD) is a type of synaptic plasticity in which the efficacy of signal transmission across a synapse is persistently reduced after a certain triggering activity. LTD in the cerebellum was proposed as a theoretical possibility around 1970 and was detected a decade later (Ito, Sakurai, and Tongroach, 1982). So far, several subtypes of LTD varying in cellular and molecular mechanisms have been found in the cerebellum, hippocampus, and neocortex. LTD occurs not only in excitatory synapses, but also in inhibitory ones. LTD may weaken or functionally interrupt useless or erroneous synaptic connections between neurons, providing an opposing mechanism against long-term potentiation (LTP) in various forms of learning and memory.


Method

Subjects

Thirty-eight male Lister Hooded rats were used as subjects. They were approximately 12 months old at the start of the study. The animals were housed in groups of four, with water constantly available in the home cage. The rats had a free-feeding body weight range of 460–600g, and were housed in groups of four, with water constantly available in the home cage. The rats were maintained at 85% of their free-feeding weight throughout the experiment. All animals were weighed every day, and they were separated from the group, and housed and fed individually, overnight, if their weight varied away from 85%.

Apparatus

Conditioning chambers

Training was conducted in four identical operant-conditioning chambers (Camden Instruments Ltd.), from which the levers had been withdrawn. The chambers were ventilated by a fan that also provided a 68-dB(A) background noise. The reinforcement, one 45-mg food pellet, was delivered to a food tray, which was covered by a clear, Perspex® hinged-flap. A micro-switch was operated when the flap was opened. A jeweled house-light was located on the center of the chamber ceiling (overhead light). Another light was located centrally on the chamber wall above the food tray (central light). Both lights were 2.8 W bulbs. Based on past studies (Reed et al., 1999), both stimuli were of equal salience.

Elevated plus maze

The EPM consisted of two open (35 cm × 12 cm) and two enclosed arms (35 cm × 12 cm × 40 cm) and a center square (12 cm × 12 cm). The maze was elevated 50 cm above the floor. Open arms were surrounded by a 0.5-cm ledge and the entire floor was covered in black rubber. A black surround was placed around the apparatus to minimize visual cues. A schematic representation of an EPM is shown in Fig. 1.

Schematic representation of an elevated-plus maze (from Augusta University http://www.augusta.edu/core/labs/sabc/elevatedplusmaze.php)

Procedure

Stimulus pre-exposure task

Phase 1 (pre-exposure) consisted of eight 30-min sessions. In each session, the subjects received ten 30-s non-reinforced exposures to a light (CSPE). For half of the subjects, the central light was used as the CSNPE, whilst the overhead light was used as the CSPE. For the other half, the central light was used as the CSPE, whilst the overhead light was used as the CSNPE. The first stimulus presentation occurred 150 s after the onset of the session. All subsequent inter-trial intervals were 150 s.

Phase 2 (conditioning) consisted of six 30-min sessions, during which all subjects received ten 30-s presentations of the CSPE, immediately followed by reinforcement. In addition, they received ten 30-s presentations of the stimulus CSNPE immediately followed by reinforcement. The presentation of the experimental events was counterbalanced using a random, computer-generated order. Responses were recorded as entries to the magazine flap. All the subjects received the same programmed events.

Elevated plus maze

On the day of testing, subjects were removed from their home cages and transported individually to the testing room. Each subject was placed in the center square facing an open arm, and was allowed to explore freely the apparatus for a period of 5 min. Each 5-min trial was videotaped, and later analyzed by a trained observer using specifically designed software (Mazetime, Oxford, UK). The analysis of rats’ behavior in the maze was undertaken “blind” to the rats’ performance after both behavioral tests were completed. The EPM was cleaned with a 20% ethanol solution between trials (Bulos, Pobbe, & Zangrossi, 2015).

A variety of behavioral measures were recorded that have been shown to selectively reflect anxiety and locomotor activity (Cruz, Frei, & Graeff, 1994 Pellow et al., 1985). Anxiety parameters are taken to be reflected in the rats’ preference for the closed sections of the maze as opposed to the open sections (Cruz et al., 1994 Pellow et al., 1985). These consist of: (a) the number of entries made by subjects into the open arms relative to overall arm entries (ratio of open-entries, ROE – i.e., number of open-arm entries/total arm-entries) and (b) the time spent by subjects on the open arms relative to overall trial duration (ratio of open-time, ROT – i.e., time spent in open-arms/overall trial duration [300 s]). Low values for these anxiety measures indicate higher anxiety, and higher values indicate lower anxiety (same preference for closed and open places). The number of entries made into closed arms relative to overall entries (ratio of closed-entries, RCE), and the time spent by subjects in the closed arms relative to overall trial duration (ratio of closed-time, RCT), were recorded as well. The locomotor measures consisted of the total number of entries into any of the maze arms (total-entries, TE), and the number of entries into the closed arms (closed-entries, CE). The subject’s location on the maze was defined as four paws being present in a maze arm. These estimate the overall activity of the rat rather than any preference for particular areas of the maze – and reflect the degree of activity of the rat independent of anxiety.