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We note with interest the recent article Acute tryptophandepletion in healthy males attenuates phasic cardiac slow-ing but does not affect electro-cortical response to negativefeedback by van der Veen et al. (2008). In that study, acutetryptophan depletion (ATD, a dietary method to transientlylower central serotonin levels) attenuated cardiac decelera-tion, possibly reflecting a decreased impact of negativefeedback stimuli due to improved punishment prediction.This is congruent with preclinical data suggesting that ATDreduces cardiopulmonary reflex bradycardia and baroreflexgain (Kellett et al. 2004).The group of van der Veen et al. has previouslyemphasised the role of higher cortical centers in ATDaction (Evers et al. 2005, 2006); we wish to underline therole of brainstem systems here. There is evidence that 5-HT-containing pathways within the brainstem can haveprofound influences on the neurones involved in control ofthe heart (Lehnert et al. 1987) and these are mediated by avariety of 5-HT receptors that act at different brainstemsites (Jeggo et al. 2005; Kellett et al. 2005). Whilst theevidence suggests that these pathways are not tonicallyactive at rest, they are recruited during several differentreflexes which modify heart rate (Jordan 2005).We have now used the ATD procedure in clinical trialsof over 100 subjects and have found it to be safe, effectiveand well-tolerated. Our protocol (Hood et al. 2005) is basedon the standard described by Young et al. (1985) withwomen consuming 80% of the mixture because of lowerbody weight (Smith et al. 1997). On two occasions,however, we have observed adverse effects that werereported to local HRECs—both of these were cardiovascu-lar side effects involving significant episodes of bradycar-dia. Unblinding of patient data revealed that these incidentsboth occurred on the ATD occasion.Case #1 is a 64-year-old woman who presented withobsessive compulsive disorder (OCD, moderate checking,counting and mild hoarding symptoms), which respondedto escitalopram 15 mg/day. She participated in a ATD studyof patients who had selective serotonin reuptake inhibitor(SSRI)-remitted OCD. There was a past history of majordepression and mild hypertension, the latter well-controlledon amlodipine 5 mg/day. On the first testing day (ATDoccasion), the study progressed uneventfully until mid-afternoon when, shortly after having a venous blood sampleextracted from an in situ cannula present in her leftantecubital fossa, she experienced a vasovagal episodelasting less than 1 min. She was nauseated immediatelyprior to this episode and a transient drop in blood pressurewas noted (from 135/84 PR 72 to 104/56 PR 67). As aprecautionary measure, a 500-mL bag of IV saline/dextrosewas administered to maintain blood pressure, and thedecision was made to abort the study (despite the patient’srequest that she felt able to continue). Over the subsequent45 min we proceeded to prepare her for discharge home tothe care of her family, and this included feeding her a dietrich in tryptophan (the study depleted the body of this), andshe consumed some of the chocolate-flavoured milk thatshe had to hand. During the procedure of putting on hershoes (which may have involved some straining), she feltnauseated again, vomited and had a second vasovagal

Piazza and Deroche-Gamonet have significantly contributed to the field of addiction and published several pioneering articles that have had a major influence on the field. The latest article by Piazza and Deroche-Gamonet is a position paper, in which they argue that they provide a foundation for the first general theory of the transition to addiction. Their theory is composed of the following three principles: (1) The transition to addiction depends on an interaction between individual vulnerability and drug exposure. (2) The transition to addiction involves at least three steps (i.e., recreational/sporadic drug use, intensified/sustained/escalated drug use, and loss of control/full addiction). (3) Addiction is a true psychiatric disease. Piazza and Deroche-Gamonet propose to test their “first” general theory of addiction by providing three predictionsthatcanbeusedtovalidateorinvalidatetheir theory.The review by Piazza and Deroche-Gamonet represents an excellent opportunity to discuss critical aspects of the transition to addiction. In this article, we attempt to test point by point the validity of their statements based on the current state of the field,withthehopethatabetterunderstandingoftheaddiction process will lead to better treatments for drug addiction. To test the validity of their claims, as suggested by Piazza and Deroche-Gamonet, it is important to define the criteria that need to be fulfilled for a novel theory to be valid. A scientific theory is a well-substantiated explanation of a phenomenon based on knowledge that has been repeatedly confirmed through observation and experimentation. Its strength is related to the diversity of phenomena it can explain and the accuracy in predicting outcomes. A scientific theory should allow for falsifiable predictions. Finally, a new theory should better explain experimental observations than previous theories and result in further testable predictions that can be confirmed. We will review each principle proposed by Piazza and Deroche-Gamonet based on each of these criteria.

Rationale Psychostimulants, including methylphenidate (MPH), are the mainstay of pharmacotherapy for attention-deficit/hyperactivity disorder (ADHD) in adults. Even though MPH is the most commonly used medication for ADHD these days, there are relatively few resources available that provide comprehensive insight into the pharmacological and clinical features of the compound. Objective The aim of this paper is to provide an up-to-date outline of the pharmacology and clinical utility of MPH for ADHD in adult patients. Methods While conducting the narrative review, we applied structured search strategies covering the two major online databases (MEDLINE and Cochrane Central Register of Controlled Trials). In addition, we performed handsearching of reference lists of relevant papers. Results Methylphenidate exhibits multimodal mechanism of action, working primarily as a dopamine and noradrenaline reuptake inhibitor. It also protects the dopaminergic system against the ongoing ‘wearing off’ (by securing a substantial reserve pool of the neurotransmitter, stored in the presynaptic vesicles). In placebo-controlled trials, MPH was shown to be moderately effective both against the core ADHD symptoms (standardized mean difference [SMD], 0.49; 95% confidence interval [CI], 0.35–0.64), and the accompanying emotion regulation deficits (SMD, 0.34; 95% CI, 0.23–0.45). The most common adverse events related to long-term treatment with MPH are decreased appetite (~ 20%), dry mouth (15%), heart palpitations (13%), gastrointestinal infections (~ 10%), and agitation/feeling restless (~ 10%). Conclusions There is substantial body of evidence to suggest that MPH is an effective and safe treatment option for adults with ADHD.

The regular consumption of very small doses of psychedelic drugs (known as microdosing) has been a source of growing media and community attention in recent years. However, there is currently limited clinical and social research evidence on the potential role of microdosing as therapies for mental and substance use disorders. This paper examined subjective experiences of microdosing psychedelics to improve mental health or to cease or reduce substance use, and examined sociodemographic and other covariates of perceived improvements in mental health that individuals attributed to microdosing. An international online survey was conducted in 2018 and examined people’s experiences of using psychedelics for self-reported therapeutic or enhancement purposes. This paper focuses on 1102 respondents who reported current or past experience of psychedelic microdosing. Twenty-one percent of respondents reported primarily microdosing as a therapy for depression, 7% for anxiety, 9% for other mental disorders and 2% for substance use cessation or reduction. Forty-four percent of respondents perceived that their mental health was “much better” as a consequence of microdosing. In a multivariate analysis, perceived improvements in mental health from microdosing were associated with a range of variables including gender, education, microdosing duration and motivations, and recent use of larger psychedelic doses. Given the promising findings of clinical trials of standard psychedelic doses as mental health therapies, clinical microdosing research is needed to determine its potential role in psychiatric treatment, and ongoing social research to better understand the use of microdosing as self-managed mental health and substance use therapies.

Human research with hallucinogens such as lysergic acid diethylamide (LSD) has been ongoing in the USA since 1949. During the 1960s, LSD was investigated for a variety of psychiatric indications, including the following: as an aid in treatment of schizophrenia; as a means of creating a "model psychosis"; as a direct antidepressant; and as an adjunct to psychotherapy. Studies with all drugs, including LSD, have always been conducted under federal regulatory controls, including the 1938 Food Drug and Cosmetic Act (FDCA; which ensured the safety of drugs) and the 1962 Kefauver-Harris Amendments to the FDCA (which described appropriate scientific methodology and ensured drug efficacy). This paper details how the 1962 Amendments introduced numerous safety and efficacy requirements that must be in satisfied during clinical drug research-and how human studies conducted with LSD in the 1960s struggled with their fulfillment. Information is provided from Senate hearings, case law, and interviews with key investigators. Examples are also drawn from scientific papers and symposia published during and since that period, with a focus on information from clinical studies conducted with LSD by psychiatrist Albert Kurland at the Spring Grove State Hospital, near Baltimore, MD. While Kurland largely conformed with these new regulations, other investigators often fell short of complying with scientific standards and federal requirements. Thus, the human hallucinogen studies of the 1960s are best understood as providing pilot data on safety and efficacy, as well as testable hypotheses for current hallucinogen studies conducted under modern scientific and regulatory standards.

Deroche-Gamonet and Piazza’s thoughtful and ambitious paper contains much that can be agreed upon. By weaving into a single narrative, theories, models and experimental findings, itsauthorshaveprovidedthe readerswitha superbsynopsisof much that has taken place in the field of addiction neuroscience over the last three decades. This paper, however, is much more than a synopsis. As befitting to any major piece of scholarly work, it is a catalyst of ideas concerning the very nature of addiction, thus triggering a number of considerations, many more than can be crammed into a commentary. Out of these considerations, possible stumbling blocks for the present theory appear to emerge. I will limit myself to highlight three sets of issues that may be of general interest to researchers in the field, one set for each of the three sections of the paper.

Current pharmacological approaches to treatment of post-traumatic stress disorder (PTSD) lack adequate effectiveness. As a result, identifying new molecular targets for drug development is necessary. Furthermore, fear learning and memory in PTSD can undergo different phases, such as fear acquisition, consolidation, and extinction. Each phase may involve different cellular pathways and brain regions. As a result, effective management of PTSD requires mindfulness of the timing of drug administration. One of the molecular targets currently under intense investigation is the N-methyl-D-aspartate (NMDA)-type glutamate receptor (NMDAR). However, despite the therapeutic efficacy of drugs targeting NMDAR, their translation into clinical use has been challenging due to their various side effects. One possible solution to this problem is to target signaling proteins downstream to NMDAR to improve targeting specificity. One of these proteins is the neuronal nitric oxide synthase (nNOS), which is activated following calcium influx through the NMDAR.In this paper, we review the literature on the pharmacological modulation of nNOS in animal models of PTSD to evaluate its therapeutic potential. Furthermore, we attempt to decipher the inconsistencies observed between the findings of these studies based on the specific phase of fear learning which they had targeted.Inhibition of nNOS may inhibit fear acquisition and recall, while not having a significant effect on fear consolidation and extinction. However, it may improve extinction consolidation or reconsolidation blockade.Modulation of nNOS has therapeutic potential against PTSD and warrants further development for use in the clinical setting.

Rationale Early Life Stress (ELS) increases risk for both adult traumatization and posttraumatic stress disorder (PTSD). Adult PTSD may also reflect a continuation of a response to an earlier exposure to adversity. Given similarities between neuroendocrine aspects of PTSD and ELS, such as in reduced cortisol signaling and glucocorticoid receptor (GR) responsiveness, some aspects of the biology of PTSD may reflect biological correlates of risk. Objectives This paper will examine how empirical findings regarding the biological basis of ELS can inform our understanding of the neuroendocrinology of PTSD. This paper will also propose a hypothetical model to guide future research that integrates genetic, epigenetic, neuroendocrine, and psychological observations to understand the contribution of ELS neurobiology to PTSD. Results Recent genetic findings demonstrate heritable aspects of at least some of these cortisol-related disturbances. Furthermore, ELS may produce at least some of the PTSD-associated changes in glucocorticoid responsiveness through epigenetic mechanisms such as developmental programming. These, then, may contribute to enduring changes in stress responsiveness as well as enhanced risk for adult exposure and PTSD. Conclusion Molecular mechanisms associated with gene x environment interactions or GR programming are essential in explaining current observations in the neuroendocrinology of PTSD that have been difficult to understand through the lens of contemporary stress theory.

Rationale. The functional analysis of the behavioral effects of drugs has lagged behind more biological research approaches in elucidating how drugs influence behavior. Part of the problem is the scarcity of mathematical models of responding under standardized behavioral procedures. A two-parameter model derived from the matching law to account for response rate as a function of reinforcement rate in single response alternative procedures provides a good description of responding under multi-component multiple variable interval (mult VI) schedules of reinforcement, both in the absence of drugs and in the presence of a variety of drugs. Objective. This paper explores how well the two-parameter model and its exponentiated variant (three-parameter model) describe drug effects on responding under mult VI schedules. Methods. Data from seven published papers concerning the effects of drugs on mult VI schedules are reanalyzed. Results. The three-parameter model describes the effects of drugs on responding more accurately than does the two-parameter model. The three-parameter model also describes well the type of relation between response rates under drug and no-drug conditions that the rate dependency hypothesis is usually invoked to explain. Conclusions. The three-parameter model can be improved by adding a parameter to account for base response rate, that is, response rate when reinforcement rate is zero. The parameters of the best descriptive model could be used to devise a classification system for the behavioral effects of drugs under mult VI schedules. The parameters should be conceptualized by relating the drug-induced changes in parameter value to converging changes in measurements of brain function. This would connect the behavioral and the biological analyses of drug action to the benefit of both research fields.

In their Letter to the Editor, Dr Loeb and colleagues describe two cases that show a substantial overlap between symptoms considered on the one hand to be catatonic phenomena and on the other to be features of neuroleptic malignant syndrome (Loeb et al. 2015). This syndromal overlap is a common challenge to clinical practitioners (Loeb et al. 2015) because early identification of the underlying disease pattern paves the way for further decisions, e.g. regarding treatment strategies. For example, benzodiazepines are most commonly used for catatonia (Rosebush and Mazurek 2010), whereas bromocriptine and dantrolene are favoured in the treatment of neuroleptic malignant syndrome (Musselman and Saely 2013; Bienvenu et al. 2012). To distinguish between these two entities, Loeb et al. (2015) successfully applied the model proposed by our research group (Lang et al. 2015). On the basis of a large sample of case reports, we were able to statistically identify several clinical signs and symptoms that have a high discriminant power for distinguishing on a descriptive level between neuroleptic malignant syndrome and catatonia. On a cautionary note, however, our findings were limited by the lack of an external validation of the physicians’ clinical diagnoses. Furthermore, it was unclear to what extent our model would be useful in clinical practice (Lang et al. 2015). Against this background, we were pleased to read in the paper by Loeb et al. (2015) that our proposed model appeared to be useful in clinical practice. The authors recommend the additional application of the Bush-Francis Catatonia Rating Scale (BPCRS, Bush et al. 1996) to identify more clearly the presence of catatonia (Loeb et al. 2015). However, this suggestion is challenged by the fact that a large proportion of patients who fulfil the DSM-IV criteria for neuroleptic malignant syndrome, according to Koch et al. 2000, also fulfil clinical criteria for catatonia according to the BFCRS. In principle, an unmistakable distinction between both entities appears to be unachievable merely at the level of cross-sectional clinical signs. Therefore, the challenge is (i) to identify neurobiological markers and (ii) to characterise patients on the basis of their long-term psychopathological course (White and Robins 2000). Thus, long-term case observations following both catatonic crises and cases of NMS could further our understanding of the NMS/catatonia dilemma. Psychomotor abnormalities are still common in patients seen in current practice, although such abnormalities may not be sufficiently taken note of, documented and valued in the diagnostic process (van der Heijden et al. 2005). At present, catatonia is considered a nosologically unspecific psychopathological syndrome rather than a distinct form of schizophrenia. The second case report in the paper by Loeb et al. (2015) bears witness to this broad use of the termwhich is also endorsed by DSM-5. We should bear in mind that psychomotor symptoms are an integral component of schizophrenia. As the traditional concept of catatonia might be too narrowly defined, new approaches to defining the concept are currently being developed (Walther and Strik 2012; Morres et al. 2014). Both clinical and research practice need to make sure that psychomotor symptoms are not only considered in the context of antipsychotic medication which clearly falls short of the mark. * Fabian U. Lang fabian.lang@uni-ulm.de

The therapeutic potential of medical cannabis to treat a variety of conditions is becoming increasingly recognised. Globally, a large number of countries have now legalised cannabis for medical uses and a substantial number of patients are able to access their medications. Yet in the UK, where medical cannabis was legalised in November 2018, only a handful of NHS prescriptions have been written, meaning that most patients are unable to access the medicine. Reasons for this are manyfold and include the perceived lack of clinical evidence due to the challenges of studying medical cannabis through randomised controlled trials. In order to develop the current evidence base, the importance of incorporating real-world data (RWD) to assess the effectiveness and efficacy of medical cannabis has gradually become recognised. The current paper provides a detailed outline of Project Twenty21 (T21), the UK’s first medical cannabis registry, launched in August 2020. We provide the rationale for T21 and describe the methodology before reporting the characteristics of the ‘first patients’ enrolled in the registry. We describe the health status of all patients enrolled into the project during its first 7 months of operation and the sociodemographic characteristics and primary presenting conditions for these patients, as well as details of the medical cannabis prescribed to these individuals. By 12th March 2021, 678 people had been enrolled into T21; the majority (64%) were male and their average age was 38.7 years (range = 18–80). The most commonly reported primary conditions were chronic pain (55.6%) and anxiety disorders (32.0%) and they reported high levels of multi-morbidity, including high rates of insomnia and depression. We also present preliminary evidence from 75 patients followed up after 3 months indicating that receipt of legal, prescribed cannabis was associated with a significant increase in self-reported health, assessed using the visual analogue scale of the EQ-5D-5L (Cohen’s d = .77, 95% CI = .51–1.03). Our initial findings complement reports from other large-scale databases globally, indicating that the current RWD is building up a pattern of evidence. With many clinicians demanding better and faster evidence to inform their decisions around prescribing medical cannabis, the current and future results of T21 will expand the existing evidence base on the effectiveness of cannabis-based medical products (CBMPs).

Cannabidiol (CBD) products lacking regulatory approval are being used to self-treat a myriad of conditions and for their unsubstantiated health benefits. The scientific evidence supporting these claims largely arises not from controlled clinical trials, but from the recognition that CBD has numerous biological targets. Yet, CBD is commonly consumed and often in over-the-counter products that are unapproved and of unknown composition. Epidiolex® is the only product that has undergone rigorous pharmacokinetic assessment and testing in clinical trials; it was approved as a non-scheduled drug by the U.S. Food and Drug Administration for the treatment of intractable childhood-onset seizures. However, studies investigating CBD for other medical conditions are limited in number and often lack the scientific rigor, controls, or sample sizes required to draw clinically meaningful conclusions. Although Epidiolex® is safe for human consumption, recent changes in regulation of commercially available CBD products have resulted in limited quality control and products marketed with unknown CBD bioavailability. Even scientifically rigorous studies have used different sources of CBD and different suspension vehicles for administration, making it difficult to compare results among studies and resolve mixed outcomes. This paper reviews the molecular targets, pharmacokinetics, and safety and abuse liability of CBD; additionally, the extant evidence on its potential therapeutic effects for neurological disorders, pain, inflammation, conditions related to immune function, psychiatric disorders, and substance use are described.

AbstractAyahuasca is a psychoactive plant brew containing dimethyltryptamine (DMT) and monoamine oxidase inhibitors (MAOIs). It originates from the Amazon basin, where it is used primarily for ceremonial purposes. Ayahuasca tourists are now entering certain communities seeking alternative physical or psychological healing, as well as spiritual growth.RationaleRecent evidence has shown that the similar acting psychedelic compound, psilocybin, facilitated long-term increases in trait openness following a single administration.ObjectivesThis paper assesses the impact of ayahuasca on personality in a traditional framework catering for ayahuasca tourists.MethodWithin a mixed design, we examined the effect of ayahuasca on participants’ personality (measured by the NEO Personality Inventory 3 questionnaire) across time (pre- to post-ayahuasca administration, and 6-month follow-up), relative to a comparison group (who did not ingest ayahuasca).ResultsThe results demonstrated significant increases in agreeableness pre- and post-ayahuasca administration and significant reductions in neuroticism in 24 participants, relative to the comparison group. Both of these changes were sustained at 6-month follow-up, and trait level increases were also observed in openness at this stage. Additionally, greater perceived mystical experience (measured using the Mystical Experience Questionnaire 30) was associated with increased reductions in neuroticism.ConclusionsThese findings, which indicate a positive mediating effect of ayahuasca on personality, support the growing literature suggesting potential therapeutic avenues for serotonergic psychedelics.

People with schizophrenia frequently have cognitive dysfunction, which does not respond to pharmacological interventions. Varenicline has been identified as a potential treatment option for nicotinic receptor dysfunction with a potential to treat cognitive impairment in schizophrenia. We conducted a systematic review of Pubmed, Embase, Psycinfo, CINAHL and the Cochrane Schizophrenia Trial Registry for randomised controlled trials of varenicline in people with schizophrenia for cognitive dysfunction. We excluded trials among people with dementia. We then undertook a meta-analysis with the primary outcome of difference in change of cognitive measures between varenicline and placebo as well as secondary outcomes of difference in rates of adverse events. We conducted a sensitivity analysis on smoking status and study duration. We included four papers in the meta-analysis (n = 339). Varenicline was not superior to placebo for overall cognition (SMD = −0.022, 95% CI −0.154–0.110; Z = −0.333; p = 0.739), attention (SMD = −0.047, 95% CI −0.199–0.104; Z = −0.613; p = 0.540), executive function (SMD = −0.060, 95% CI −0.469–0.348; Z =− 0.290; p = 0.772) or processing speed (SMD = 0.038, 95% CI −0.232–0.308; Z = 0.279; p = 0.780). There was no difference in psychotic symptoms, but varenicline was associated with higher rates of nausea. Sensitivity analyses for smoking status and study duration did not alter the results. Within the present literature, varenicline does not appear to be a useful target compound for improving cognitive impairment in schizophrenia. Based on these results, a trial would need over 2500 participants to be powered to show statistically significant findings.

This paper evaluates the arguments put forward by Robinson and Pritchard (R&P, this volume) that the conclusions of the US Surgeon General (USDHHS 1988) that nicotine is addictive were ill founded. R&P state that nicotine does not cause intoxication, that many smokers do not exhibit compulsive use, that nicotine is not a euphoriant, that nicotine is a weak reinforcer in other species, that non-pharmacological aspects of smoking are important and that negative affect control accounts for more of the variance in questionnaire measures of smoking motives than does habit. This paper points out that intoxication and a euphoriant effect are not normally considered to be central to dependence potential, that no addictive drug results in compulsive use in all users in all situations, that animals do reliably self-administer nicotine, that evidence concerning the apparent importance of non-pharmacological components of smoking do not diminish the importance of pharmacological aspects and that "variance accounted for" of self-report measures of smoking motivation do not bear on the issue of the importance of those motives. The paper concludes with a summary of the essence of the argument that cigarettes are addictive and that nicotine is the primary focus of that addiction.

With great interest, we have read the letter ‘Cardiac slowing and acute tryptophan depletion: a comment on the paper by van der Veen et al.’ by Hood et al. This letter is a comment on a recent paper by our group (van der Veen et al. 2008) describing the differential effects of acute tryptophan depletion (ATD) on cardiac and electro-cortical measures of performance monitoring. In the letter, the authors describe two specific cases in which ATD led to serious but transient cardiovascular side effects. These side effects involved significant episodes of bradycardia and in both cases, extra medical help had to be summoned. The authors present the cases as further evidence for an important role of serotonin in the cardiovascular system and underline the importance of cardiovascular screening of subjects participating in ATD procedures. We completely agree with the conclusions and think it is important to take note of the two described cases. However, we would like to stress that the important role of serotonin in cardiovascular regulation is well known (e.g., Jordan 2005; Dergacheva et al. 2007; Ramage and Villalon 2008) and was already briefly mentioned in our paper. Furthermore, the participants in our studies are always thoroughly screened for cardiovascular and other health problems. Finally, the described cases seem to be very atypical and that the cardiovascular side effects are most likely unrelated to the effects on heart rate in our study. Both the described cases had cardiovascular abnormalities before the start of the experiment and perhaps more thorough screening might have led to exclusion of these two patients. Moreover, both cases were psychiatric patients with a history of medication use, which might have contributed to a pre-existing cardiovascular vulnerability. Besides the ATD manipulation, case 2 was also given an infusion of the benzodiazepine antagonist flumazenil, which might have further added to any pre-existing vulnerabilities. Therefore, we think that the described patients are not the typical volunteers who participate in ATD studies, and that a combination of factors might have added to the effects of ATD. In all the studies performed by our group, in which we have included thoroughly screened healthy volunteers with or without a family history of depression, we have never encountered cardiovascular side effects of our procedures. However, it should be noted that we have incidentally encountered physical side effects such as nausea and vomiting and that these side effects have led to incidental dropout. The described cardiovascular side effects are most likely unrelated to the effects described in our study. There is strong evidence for a role of serotonin in the brain circuits involved in feedback processing (e.g., Cools et al. 2008; Jocham and Ullsperger 2009) and cardiac responses to feedback are highly sensitive to subtle changes in activation in these circuits (e.g., Crone et al. 2003; van der Veen et al. 2004). Therefore, we like to argue that the cardiac effects described in our paper are related to changes in these Psychopharmacology (2009) 203:835–836 DOI 10.1007/s00213-008-1429-8

The study by Griffiths et al. is noteworthy both for the rigorousness of its design and execution, as well as the clarity of its results. It demonstrates that psilocybin can be safely studied in normal human beings who do not have a history of hallucinogenic drug use. As would be expected, during the psilocybin session participants showed perceptual changes and labile mood. It is striking that majority of the participants reported 2 months later that the psilocybininduced experience was personally very meaningful and spiritually significant. Indeed, most of them rated the psilocybin-induced experience as one of the top five most important experiences in their life. It is especially notable that participants reported that the drug produced positive changes in attitudes and behaviors well after the sessions, and these self-observations were consistent with ratings by friends and relatives. These participants were well-prepared for the psilocybin experience by an experienced monitor, who expressly stated that psilocybin might produce increased personal awareness and insight. However, it is clear that the effects of psilocybin were more than expectancy effects because the active drug control condition (40 mg of methylphenidate) did not produce similar effects on ratings of significance or on measures of spirituality, positive attitude, or behavior. The term psychedelic, when applied to drugs, implies that the drug experience is “mind-expanding.” The paper by Griffiths et al. illustrates the accuracy of this description for psilocybin, and I hope that this landmark paper will also be “field-expanding.” The report clearly demonstrates that we can objectively study the experiences reported by many to be profoundly spiritual and meaningful, and that we can investigate the long-term positive consequences for the individual’s attitudes and behavior. It will open the way to study the neural mechanisms responsible for these drugaltered states of consciousness. It is entirely conceivable that psychotropic agents that produce these experiences may have a role in the treatment of addictive states. Spirituality has long been a major component of the 12step approach to the treatment of alcoholism and other forms of drug addiction. Although the investigations of LSD for the treatment of alcoholism failed to show any clear-cut significant beneficial effects, the possibility that a spiritual experience, such as that reported in the present study, might be useful cannot be discounted. The set and setting in which the drug is administered may dramatically alter the drug experience. In the present study by Griffiths et al., the set was well-established for a positive experience by the preparatory sessions with the monitor, and the setting was one that was designed to produce an introspective state. This may be an important determinant of the experience and could well alter any possible therapeutic efficacy. The possibility of easing the ennui and anguish of impending death with agents such as psilocybin is also suggested in the study by Kast (1966) and those that are reviewed in the commentary of Professor Nichols. It is likely that psilocybin might have the same salutary effects. This is not an insignificant issue especially considering the large numbers of aging individuals in our society who may be in need of hospice care. In summary, I hope that this paper by Griffiths et al. renews interest in a fascinating and potentially useful class of psychotropic agents. The misuse of these substances that led to their control in Schedule I of the Controlled Substances Act cannot be allowed to continue to curtail their use as tools for understanding the neurobiology of Psychopharmacology DOI 10.1007/s00213-006-0460-x

Interest in cognition in schizophrenia has skyrocketed in the past decade, as evidenced by this special issue. This issue is partially based on presentations made at the 5th Biennial Mount Sinai Conference on Cognition in Schizophrenia, in April 2001 in Whistler, B.C., Canada. The first Mount Sinai Meeting in 1993 had 27 attendees and the one in Whistler (from which this issue originated) had 298. The latest meeting, in Colorado Springs in 2003, had 315 attendees. The number of publications on the topic has increased as well, with some journal editors noting that the majority of papers on schizophrenia submitted to their journals are focused on cognitive functioning. The number of papers on cognition in schizophrenia published and presented at major meetings has increased as much as 5-fold in the past 15 years. Further, the NIH has recently acknowledged (Hyman and Fenton 2003) that treatment of cognitive impairment with pharmacological means is an important intervention target, as evidenced by several recent initiatives that are aimed at the treatment of cognitive impairment in schizophrenia through various means. This increase in interest can be traced to two emerging trends. The first is the increased understanding of the functional importance of cognitive impairments in schizophrenia, where it is now widely accepted, in the scientific if not the clinical community, that cognitive impairments are the primary determinant of functional deficits in schizophrenia (e.g. Green 1996; Harvey et al. 1998; Green et al. 2000). Since functional limitations in the illness are responsible for much of the disability that occurs, this is an important revelation and one that has moved the study of cognition in schizophrenia outside the realm of an academic exercise. The second important trend in the field is the increased interest in the neurobiology and treatment of cognitive impairment in schizophrenia. If cognitive deficits are the determinants of functional limitations, it seems logical that treatment of cognitive deficits would lead, all other things equal, to functional improvements. Treatments can be either behavioral in nature or pharmacologically based. Rational pharmacology will progress the most rapidly with the understanding of biological substrates of cognitive impairments. This Special Issue is multifaceted in its topics. They arise from three different sources, including presentations made at the Mount Sinai conference in 2001, articles spontaneously submitted to the journal that addressed the neural bases of cognitive impairments in schizophrenia, and articles that address basic science topics that are relevant to cognitive impairments similar to those seen in schizophrenia. There are three different sections in this issue. The sections include studies of NMDA receptor manipulations, pharmacological manipulation of prepulse inhibition and latent inhibition, and treatment of cognitive impairments in schizophrenia, with a final article describing the US National Institute of Health’s large-scale project on Measurement and Treatment Research Involving Cognition in Schizophrenia (MATRICS). This project itself arises from the increased recognition of the fact that treating cognition in schizophrenia may be the path to improvement in functional outcome in the illness. While mice are not men and a widely useful animal model of schizophrenia in general has proven difficult to develop, we believe that the usefulness of animal models P. D. Harvey ()) Department of Psychiatry, Mt. Sinai School of Medicine, Box 1229, New York, NY 10029, USA e-mail: pdharvey@compuserve.com

Many physiological and pathological changes in brain function manifest in eye-movement control. As such, assessment of oculomotion is an invaluable part of a clinical examination and affords a non-invasive window on several key aspects of neuronal computation. While oculomotion is often used to detect deficits of the sort associated with vascular or neoplastic events; subtler (e.g. pharmacological) effects on neuronal processing also induce oculomotor changes. We have previously framed oculomotor control as part of active vision, namely, a process of inference comprising two distinct but related challenges. The first is inferring where to look, and the second is inferring how to implement the selected action. In this paper, we draw from recent theoretical work on the neuromodulatory control of active inference. This allows us to simulate the sort of changes we would expect in oculomotor behaviour, following pharmacological enhancement or suppression of key neuromodulators-in terms of deciding where to look and the ensuing trajectory of the eye movement itself. We focus upon the influence of cholinergic and GABAergic agents on the speed of saccades, and consider dopaminergic and noradrenergic effects on more complex, memory-guided, behaviour. In principle, a computational approach to understanding the relationship between pharmacology and oculomotor behaviour affords the opportunity to estimate the influence of a given pharmaceutical upon neuronal function, and to use this to optimise therapeutic interventions on an individual basis.

The basolateral amygdala complex (BLA) and infralimbic region of the prefrontal cortex (IL) play distinct roles in the extinction of Pavlovian conditioned fear in laboratory rodents. In the past decade, research in our laboratory has examined the roles of these brain regions in the re-extinction of conditioned fear: i.e., extinction of fear that is restored through re-conditioning of the conditioned stimulus (CS) or changes in the physical and temporal context of extinction training (i.e., extinction of renewed or spontaneously recovered fear). This paper reviews this research. It has revealed two major findings. First, in contrast to the acquisition of fear extinction, which usually requires neuronal activity in the BLA but not IL, the acquisition of fear re-extinction requires neuronal activity in the IL but can occur independently of neuronal activity in the BLA. Second, the role of the IL in fear extinction is determined by the training history of the CS: i.e., if the CS was novel prior to its fear conditioning (i.e., it had not been trained), the acquisition of fear extinction does not require the IL; if, however, the prior training of the CS included a series of CS-alone exposures (e.g., if the CS had been pre-exposed), the acquisition of fear extinction was facilitated by pharmacological stimulation of the IL. Together, these results were taken to imply that a memory of CS-alone exposures is stored in the IL, survives fear conditioning of the CS, and can be retrieved and strengthened during extinction or re-extinction of that CS (regardless of whether the extinction is first- or second-learned). Hence, under these circumstances, the initial extinction of fear to the CS can be facilitated by pharmacological stimulation of the IL, and re-extinction of fear to the CS can occur in the absence of a functioning BLA.

In order to assess the risk associated with early-life stress, there has been an increase in the amount of preclinical studies investigating early-life stress. There are many challenges associated with investigating early-life stress in animal models and ensuring that such models are appropriate and clinically relevant. The purpose of this review is to highlight the methodological considerations in the design of preclinical studies investigating the effects of early-life stress on alcohol and psychomotor-stimulant intake and behaviour. The protocols employed for exploring early-life stress were investigated and summarised. Experimental variables include animals, stress models, and endpoints employed. The findings in this paper suggest that there is little consistency among these studies and so the interpretation of these results may not be as clinically relevant as previously thought. The standardisation of these simple stress procedures means that results will be more comparable between studies and that results generated will give us a more robust understanding of what can and may be happening in the human and veterinary clinic.

A very large number of reports have accumulated in the field relating to dopamine receptors and connected issues. For example, more than 3000 reports relating to "dopamine" are cited in MEDLINE, the database of the US National Library of Medicine (1992). Even when limited to "dopamine receptor", the number of the reports is still over 800. In such a situation, we feel it is important that we select only effective and important reports to achieve good citations. Redundant sentences should be avoided and the number of references should be kept to a reasonable minimum. A great number of papers illustrate that D-I blockade causes catalepsy. The report of Christensen et al. (1984) is recognized as the pioneer, and therefore we referred to their paper in the context of our own (Wanibuchi and Usuda 1990). Numerous reports agree with the fact that cholinergic systems in the brain are involved in catalepsy induced by dopamine antagonists. This is generally accepted. Although this cholinergic involvement was not the main theme in our paper, we wanted to state that research relating to the cholinergic system in catalepsy has started to take a new turn. In recent years, five genes that encode muscarinic acetylcholine receptor subtypes have been found to be present in the brain and they have been isolated. Evidence is accumulating that distributions of their mRNAs are abundant in specific areas of the brain (Mei et al. 1989). Immunocytochemistry has demonstrated that m1-, m2or m4-receptor proteins are distributed in various regions in the brain including striaturn and substantia nigra (Levey et al. 1991). It is likely, therefore, that these receptor subtypes could play important roles in the interaction between the cholinergic and dopaminergic systems. Although selective agents for each of the five mnscarinic receptor subtypes are not available, complex interactions among these muscarinic and dopaminergic receptors may be clarified by using the recently reported selective muscarinic agents in combination (Fifth International Symposium on Subtypes of Muscarinic Receptors 1992).

Knowing how stress manifests in the lives of people with substance-use disorders could help inform mobile “just in time” treatment. The purpose of this paper is to examine discrete episodes of stress, as distinct from the fluctuations in background stress assessed in most EMA studies. For up to 16 weeks, outpatients on opioid-agonist treatment carried smartphones on which they initiated an entry whenever they experienced a stressful event (SE) and when randomly prompted (RP) three times daily. Participants reported the severity of stress and craving and the context of the report (location, activities, companions). Decomposition of covariance was used to separate within-person from between-person effects; r effect sizes below are within-person. Participants (158 of 182; 87%) made 1787 stress-event entries. Craving for opioids increased with stress severity (r effect = 0.50). Stress events tended to occur in social company (with acquaintances, 0.63, friends, 0.17, or on the phone, 0.41) rather than with family (spouse, −0.14; child, −0.18), and in places with more overall activity (bars, 0.32; outside, 0.28; walking, 0.28) and more likelihood of unexpected experiences (with strangers, 0.17). Being on the internet was slightly protective (−0.22). Our prior finding that being at the workplace protects against background stress in our participants was partly supported in these stressful-event data. The contexts of specific stressful events differ from those we have seen in prior studies of ongoing background stress. However, both are associated with drug craving.

We have shown that differences in the level of neural activation to stimuli associated with smoking vs. natural rewards, a biomarker related to reward sensitivity, predict treatment outcome. This paper examined whether this biomarker moderates the impact of bupropion or varenicline on smoking cessation. Prior to treatment randomization, smokers (N = 180) in a placebo-controlled trial using bupropion and varenicline completed event-related potential recording (late positive potential, LPP) while viewing pleasant (P), cigarette (C)-related, and other pictures. We used Bayesian models to estimate the probability of interaction between treatment and the LPP for both efficacy and comparative effectiveness analyses. Efficacy analysis showed that smokers with more neural activation to pleasant vs. cigarette-related stimuli (P > C) had a 98–99% chance of achieving greater abstinence than placebo (OR >1.00), using either medication from the end of treatment (EOT, primary outcome) through the 3-month follow-up. Relative to placebo, smokers with higher activation to cigarette-related vs. pleasant stimuli (C > P) had a 99% chance of increased benefit from varenicline at both time points (OR >1), but only 67 and 43% with bupropion at the EOT and 3-month follow-up, respectively. Comparative effectiveness analysis found that smokers with the C > P activation pattern had a 95–98% chance of benefit from varenicline vs. bupropion, while P > C smokers had a 50–58% chance of similar improvement with varenicline at the EOT and 3 months. Varenicline appears to be the treatment of choice for smokers with the C > P pattern of neural activation, while for those showing P > C, varenicline and bupropion have similar efficacy.

The contributions of Weiner and Feldon are seminal to the literature on latent inhibition (LI). We recognized the priority of their work, theoretical and experimental, in our introduction. Our introduction is a very succint effort to provide a rationale for the use of LI as an animal behavioral model of antipsychotic drug action to a reader new to the paradigm. It is not an inclusive review of the literature. The prominent position of the work of Weiner and Feldon on LI and its use in understanding drug effects on attention, particularly as they relate to schizophrenia, is such that we did not feel the issue of precedence needed to be addressed in any greater detail. Our paper derives from the work of Christison et al. (1988), which was ongoing at the time of Weiner and Feldon's 1987 publication on haloperidol enhancement of LI. It was presented in part in 1989 as noted in the paper. Though it follows Weiner and Feldon's 1987 and 1991 publications, it is not accurate to suggest that it is derived from those works. I applaud Dr. Weiner and Dr. Feldon's finding that LI is enhanced by clozapine in their paradigm. This important finding strengthens the use of LI in antipsychotic drug discovery. I look forward to reading more about their ability to tap into the atypical profile of clozapine. I disagree with their comments about the lack of enhancement we reported after acute haloperidol treatment. I stand by our argument that this finding was an artifact resulting from the effort to balance vehicle treatment effects between animals treated for varying lengths of time. Inspection of our Fig. 2 supports this view. We stressed in the paper that these findings should be interpreted as an increase in LI effect with prolonged treatment rather than a lack of acute effect. We have data showing enhancement of LI by acute haloperidol treatment at a dose of 0.3 mg/kg using the same procedure described in our paper. Results were: haloperidot 0 PE 0.021 SE=0.002 n=10 haloperidol 20 PE 0.318 SE=0.020 n=l 1 vehicle 0 PE 0.122 SE=0.020 n=10 vehicle 20 PE 0. t90 SE=0.024 n=10 LI was enhanced (t=2.265, P0.025). We did not include this data as we felt the other data set (with six daily vehicle injections followed by an acute haloperidol injection) was logically more appropriate for comparison to the other treatment groups. Also, we have data showing a clear disruption of LI following acute administration of amphetamine (0.75 mg/kg free base, IR 15 rain before pre-exposure) again using the same paradigm. Results were: amphetamine 0 PE amphetamine 20 PE vehicle 0 PE vehicle 20 PE 0.008 SE=0.001 n=7 0.164 SE=0.028 n=7 0.060 SE=0.021 n=6 0.298 SE=0.016 n=7 LI was disrupted (t=2.112, P0.025). We performed these studies as pilot work to assure ourselves that our paradigm maintained aspects of face and construct validity demonstrated for other LI procedures reported in the literature. In general we have found that 7-day drug administration improves the stability and reduces variance in measurements of drug effects by allowing some tolerance to develop to sedation and motor effects of the drugs, and better acclimation to handling associated with training, testing and drug injection. I do not believe the observed differences between our paradigm and Weiner and Feldon's are a result of one session versus two sessions for pre-exposure and conditioning. LI paradigms are exquisitely sensitive to procedural parameters. Such differences as tone versus light, number and length of the CS, CS and US intensities, different parameters for defining suppression ratios, drug timing and delivery, and age and strain of the rats used can alter the experimental outcomes. Not all of these parameters are fully explored in the literature on LI, though many are reviewed by Lubow (1989). I would agree in general with Weiner and Feldon's final comment, but would broaden it to say that all of the parameters of an LI procedure should be taken into consideration when evaluating the effect of drug administration on LI.

After publication of this paper, the authors determined an error in the funding information section CX17008-CDA2 should be CX001790 (MK).

Rate dependence refers to an orderly relationship between a baseline measure of behavior and the change in that behavior following an intervention. The most frequently observed rate-dependent effect is an inverse relationship between the baseline rate of behavior and response rates following an intervention. A previous report of rate dependence in delay discounting suggests that the discounting of delayed reinforcers, and perhaps, other impulsivity measures, may change rate dependently following acute and chronic administration of potentially therapeutic medications in both preclinical and clinical studies. The aim of the current paper was to review the effects of stimulants on delay discounting and other impulsivity tasks. All studies identified from the literature were required to include (1) an objective measure of impulsivity; (2) administration of amphetamine, methylphenidate, or modafinil; (3) presentation of a pre- and postdrug administration impulsivity measure; and (4) the report of individual drug effects or results in groups split by baseline or vehicle impulsivity. Twenty-five research reports were then reanalyzed for evidence consistent with rate dependence. Of the total possible instances, 67 % produced results consistent with rate dependence. Specifically, 72, 45, and 80 % of the data sets were consistent with rate dependence following amphetamine, methylphenidate, and modafinil administration, respectively. These results suggest that rate dependence is a more robust phenomenon than reported in the literature. Impulsivity studies should consider this quantitative signature as a process to determine the effects of variables and as a potential prognostic tool to evaluate the effectiveness of future interventions.

New research findings in the field of neuroactive steroids strongly suggest that to understand their role in physiopathology, it is essential to accurately measure their tissue levels. Through his broad chemical expertise and extensive knowledge of steroids, Dr. Robert H. Purdy pioneered structure-activity relationship studies on these compounds and developed innovative detection assays that are essential to assess their function in biological tissues. The goal of the present paper is to point out the specific contributions of Dr. Purdy and his collaborators to the current knowledge on the role of neuroactive steroids in the modulation of memory and alcohol- and stress-related effects with particular emphasis on the detection assays he developed to assess their endogenous levels. Reviewed here are the major results as well as the original and valuable methodological strategies issued by the long-term collaboration between Dr Purdy and many scientists worldwide on the investigation of the structure-activity relationship of neuroactive steroids. Altogether, the data presented herein put forward the original notion that knowledge of the chemical structure of steroids is essential for their detection and the understanding of their role in physiological and pathological conditions, including the stress response. The current challenge is to identify and quantify using appropriate methods neuroactive steroids in the context of both animal and clinical studies in order to reveal how their levels change under physiological and disease states. Dr. Purdy passed away in September 2012, but scientists all over the world will always be grateful for his pioneering work on steroid chemistry and for his great enthusiasm in research.

Zolpidem is a positive allosteric modulator of γ-aminobutyric acid (GABA) with preferential binding affinity and efficacy for α1-subunit containing GABA(A) receptors (α1-GABA(A)Rs). Over the last three decades, a variety of animal models and experimental procedures have been used in an attempt to relate the behavioral profile of zolpidem and classic benzodiazepines (BZs) to their interaction with α1-GABA(A)Rs.This paper reviews the results of rodent and non-human primate studies that have evaluated the effects of zolpidem on motor behaviors, anxiety, memory, food and fluid intake, and electroencephalogram (EEG) sleep patterns. Also included are studies that examined zolpidem's discriminative, reinforcing, and anticonvulsant effects as well as behavioral signs of tolerance and withdrawal.The literature reviewed indicates that α1-GABA(A)Rs play a principle role in mediating the hypothermic, ataxic-like, locomotor- and memory-impairing effects of zolpidem and BZs. Evidence also suggests that α1-GABA(A)Rs play partial roles in the hypnotic, EEG sleep, anticonvulsant effects, and anxiolytic-like of zolpidem and diazepam. These studies also indicate that α1-GABA(A)Rs play a more prominent role in mediating the discriminative stimulus, reinforcing, hyperphagic, and withdrawal effects of zolpidem and BZs in primates than in rodents.The psychopharmacological data from both rodents and non-human primates suggest that zolpidem has a unique pharmacological profile when compared with classic BZs. The literature reviewed here provides an important framework for studying the role of different GABA(A)R subtypes in the behavioral effects of BZ-type drugs and helps guide the development of new pharmaceutical agents for disorders currently treated with BZ-type drugs.

After publication of this paper, the authors determined an error in Fig. 4. Below is the correct Fig. 4.

After publication of this paper, the authors determined an error in Fig. 3. Below is the correct Fig. 3.

Amyotrophic lateral sclerosis (ALS), one of the most common neuromuscular disorders, is characterized by the progressive degeneration of motor neurons. Although riluzole is to date the only drug that prolongs the survival, its efficacy is limited. A meta-analysis showed that riluzole represented a 9 % gain in the probability of surviving 1 year (49 % in the placebo group and 58 % in the riluzole group) and that riluzole increased median survival from 11.8 to 14.8 months (Miller et al. 2012). Thus, riluzole is reasonably safe and probably prolongs median survival by about 2 to 3 months in ALS patients (Miller et al. 2012). There was also a small beneficial effect on both bulbar and limb function, but not on muscle strength (Miller et al. 2012). In contrast, a threefold increase in serum alanine transferase was more frequent in riluzole-treated patients than controls (Miller et al. 2012). Taken together, there is a critical unmet need for novel therapeutic drugs for ALS. Understanding the cellular and molecular mechanisms underpinning the pathogenesis of ALS is, therefore, key to the discovery of novel therapeutic drugs. Accumulating evidence suggests the role of the ephrin receptor (Eph)—ephrin signaling in a range of chronic and neurodegenerative diseases (Boyd et al. 2014). EphA4, a subtype of Eph, plays a key role in the synaptic plasticity by modulating the neuron-glia cell communication that affects dendritic spine morphology (Boyd et al. 2014). A recent paper demonstrated that EphA4 plays a critical role in the motor neuron degeneration and disease progression in ALS (Fig. 1) (Van Hoecke et al. 2012). Genetic deletion of the EphA4 allele in a human superoxide dismutase 1 (SOD1) mutant model of ALS improved survival and slowed motor neuron deterioration after the onset of disease. In addition, intracerebroventricular administration of EphA4-blocking peptide into ALS rats that overexpress human mutant SOD1 delays the onset of disease and enhances survival. Expression of EphA4 in the ALS model mice was higher in large motor neurons compared to small motor neurons, and the protective effects of EphA4 gene deletion was more prominent in large motor neurons. Interestingly, in ALS patients, EphA4 expression inversely correlated with disease onset and survival and loss-of-function mutations in the EPHA4 gene are associated with long survival (Van Hoecke et al. 2012). Taken together, it is likely that EphA4 genetically modulates the vulnerability of motor neurons to axonal degeneration and that lowering EphA4 expression or inhibiting EphA4 signaling could reduce disease severity in ALS patients, delay the onset of the disease, and improve survival (Van Hoecke et al. 2012). Given the key role of EphA4 in the pathogenesis of ALS, it is likely that EphA4 inhibitors would be potential therapeutic drugs for ALS (Fig. 1). Uncaria rhynchophylla (Miq) Jack (UR) is a traditional Chinese medicine that has been used to treat cardiovascular disorder and central nervous system disorders in China (Zhou and Zhou 2010). The alkaloid rhynchophylline (Fig. 1), the major component of the extracts ofUncaria species (Gouteng in Chinese), has a potent neuroprotective action (Zhou and Zhou 2010). This is also a major component of traditional * Kenji Hashimoto hashimoto@faculty.chiba-u.jp

While stress is often proposed to play a significant role in influencing alcohol consumption, the relationship between stress and alcohol is complex and poorly understood. Over several decades, stress effects on alcohol drinking have been studied using a variety of animal models and experimental procedures, yet this large body of literature has generally produced equivocal results.This paper reviews results from animal studies in which alcohol consumption is evaluated under conditions of acute/sub-chronic stress exposure or models of chronic stress exposure. Evidence also is presented indicating that chronic intermittent alcohol exposure serves as a stressor that consequently influences drinking.The effects of various acute/sub-chronic stress procedures on alcohol consumption have generally been mixed, but most study outcomes suggest either no effect or decreased alcohol consumption. In contrast, most studies indicate that chronic stress, especially when administered early in development, results in elevated drinking later in adulthood. Chronic alcohol exposure constitutes a potent stressor itself, and models of chronic intermittent alcohol exposure reliably produce escalation of voluntary alcohol consumption.A complex and dynamic interplay among a wide array of genetic, biological, and environmental factors govern stress responses, regulation of alcohol drinking, and the circumstances in which stress modulates alcohol consumption. Suggestions for future directions and new approaches are presented that may aid in developing more sensitive and valid animal models that not only better mimic the clinical situation, but also provide greater understanding of mechanisms that underlie the complexity of stress effects on alcohol drinking.

Attention deficit/hyperactivity disorder (ADHD) is a common neurobehavioral and neuropsychiatric disorder in school-age children, and recent studies provide evidence implicating the metabolic abnormalities of dopamine (DA) for its pathophysiology. Methylphenidate, a kind of psychostimulant, is widely used in the treatment of ADHD, but some patients do not respond to it or cannot bear its side effects. As a traditional Chinese medicine preparation, Ningdong granule (NDG) has been used in the treatment of ADHD for several years in China. However, a systematical pharmacological study on its safety and mechanism still remains obscure. This paper aims to evaluate the efficiency, safety, and possible mechanism of NDG on ADHD children compared to methylphenidate. Seventy-two ADHD children were recruited to perform an 8-week, randomized, methylphenidate-controlled, doubled-blinded trial. The subjects were equally assigned to two groups receiving either NDG 5 mg/kg/day or methylphenidate 1 mg/kg/day for 8 weeks. The efficiency was assessed by the Teacher and Parent ADHD Rating Scales every 2 weeks for a total of 8 weeks. The side effects were recorded during the study. Blood, urine, and stool routine samples, liver and renal function test, and DA and homovanillic acid (HVA) concentration in sera were tested at the beginning and end of the trial. NDG ameliorated ADHD symptoms after an 8-week medication with fewer side effects compared to methylphenidate (P

Prior reviews have examined how stress, broadly defined, interacts with genetic diathesis in the pathogenesis of internalizing (i.e., depressive and anxiety) disorders. Recent findings have suggested a unique role for early life stress (ELS) in the development of internalizing disorders, contributing to the rapid proliferation of research in this area.This paper critically reviews studies in humans examining gene-environment interaction (GxE) effects of ELS on the risk for depression and anxiety, primarily from a candidate gene perspective. Major methodological challenges that are unique to such studies are considered.The majority of published studies have focused on candidates that regulate the serotonin system, especially the serotonin transporter. More recent work has addressed interactions of ELS with candidates from the hypothalamic-pituitary-adrenal axis and neurotrophin system. Available studies vary greatly with respect to definitions of ELS, examination of gene-gene interactions, consideration of gender effects, and attention to analytic limitations.Overall, there is support for GxE effects of ELS on the risk for depressive and anxiety outcomes. Future studies of ELS in this context will require careful attention to methodologic considerations. Such studies would benefit from more systematic assessment of positive environmental factors (e.g., social support) and greater utilization of developmentally sensitive paradigms.

After publication of this paper, the authors determined an error in the calculation of the norepinephrine standard concentrations for the HPLC calibration curves.

Pain is a complex sensory experience, involving cognitive factors, environment (setting, society, and culture), experience, and gender and is modulated significantly by the central nervous system (CNS). The mechanisms by which opioid analgesics work are understood, but this class of drugs is not ideal as either an analgesic or anti-hyperalgesic. Accordingly, considerable effort continues to be directed at improved understanding of nociceptor function and development of selective analgesics that do not have the unwanted effects associated with opioid analgesics. The purpose of this paper is to provide a review of the role of KOP receptors in the modulation of pain and highlight several chemotypes currently being explored as peripherally restricted KOP ligands. A growing body of literature has shown that KOP receptors are implicated in a variety of behavioral pain models. Several different classes of peripherally restricted peptidic and nonpeptidic KOP agonists have been identified and show utility in treating painful conditions. The pharmacological profile of KOP agonists in visceral pain models suggest that peripherally restricted KOP agonists are potentially useful for a variety of peripheral pain states. Further, clinical investigation of peripherally restricted KOP agonists will help to clarify the painful conditions where KOP agonists will be most effective.

Growing proportions of smokers in the USA do not smoke everyday and can be referred to as light and intermittent smokers (LITS). Despite a current prevalence of LITS in the USA estimated at 25-33% of all smokers, a systematic review of the literature on this group of smokers has yet to be written.The aim of this paper is to review and evaluate research on LITS and to identify, describe and discuss commonalities and differences between LITS and daily smokers.The primary databases used to search for publications were Pub Med (National Library of Medicine) and SCOPUS (Elsevier).LITS inhale smoke and have post-smoking blood nicotine concentrations that are broadly equivalent to those found in daily smokers. However, LITS differ from daily smokers with regard to cigarette consumption and frequency of cigarette use, sociodemographic and socioeconomic characteristics, motives, personality traits, dependence, withdrawal and craving, response to smoking-related cues, quitting perception, past-smoking status, and initiation.In contrast to daily smokers, LITS show few or no signs of dependence as currently defined by DSM-IV criteria, appear to exercise more self-control, seem to be less impulsive, and their smoking experience is primarily associated with positive rather than negative reinforcement. Conclusions drawn from the reviewed literature highlight the multivariate factors that must be taken into account when defining LITS and emphasize the importance of further research on this increasing fraction of smokers. The potential implications of increased LITS prevalence on smoking-related disease risks remain to be thoroughly investigated.

The 5-HT(7) receptor is a more recently discovered G-protein-coupled receptor for serotonin. The functions and possible clinical relevance of this receptor are not yet fully understood.The present paper reviews to what extent the use of animal models of human psychiatric and neurological disorders have implicated the 5-HT(7) receptor in such disorders. The studies have used a combination of pharmacological and genetic tools targeting the receptor to evaluate effects on behavior.Models of anxiety and schizophrenia have yielded mixed results with no clear role for the 5-HT(7) receptor described in these disorders. Some data are available for epilepsy, migraine, and pain but it is still very early to draw any definitive conclusions. There is a considerable amount of evidence supporting a role for the 5-HT(7) receptor in depression. Both blockade and inactivation of the receptor have resulted in an antidepressant-like profile in models of depression. Supporting evidence has also been obtained in sleep studies. Especially interesting are the augmented effects achieved by combining antidepressants and 5-HT(7) receptor antagonists. The antidepressant effect of amisulpride has been shown to most likely be mediated by the 5-HT(7) receptor.The use of pharmacological and genetic tools in preclinical animal models strongly supports a role for the 5-HT(7) receptor in depression. Indirect evidence exists showing that 5-HT(7) receptor antagonism is clinically useful in the treatment of depression. Available data also indicate a possible involvement of the 5-HT(7) receptor in anxiety, epilepsy, pain, and schizophrenia.

Research in rodents and non-human primates implicates the noradrenergic system and hypothalamic–pituitary–adrenal axis in stress, anxiety, and attention to threat. Few studies examine how these two neurochemical systems interact to influence anxiety and attention in humans. The objective of this paper is to examine the effects of exogenous yohimbine and hydrocortisone, as well as their combination (Y + H), on panic symptoms and attention to social threat cues. Thirty-two healthy adults underwent a pharmacological challenge in which they were blindly randomized to either yohimbine, hydrocortisone, Y + H, or placebo. Thirty minutes after drug infusion, attention to threat was measured using the dot probe task, a visual attention task that presents angry, happy, and neutral faces and measures the degree of attention allocated towards or away from the emotional faces. Panic and autonomic measures were assessed before and 30 min after drug infusion. There was a significant increase in panic symptoms in the yohimbine and Y + H groups, but not in the hydrocortisone or placebo groups. Yohimbine resulted in a greater increase in panic symptoms than Y + H. On the dot probe task, the placebo group exhibited an attention bias to angry faces, whereas this bias was absent after yohimbine. When collapsing across groups, increased panic symptoms was associated with less attention to angry faces. Exogenous hydrocortisone may attenuate noradrenergic-induced panic symptoms. The inverse relationship between panic symptoms and attention to angry faces extends prior research demonstrating attention modulation by stressful conditions.