Progress in Neuro-Psychopharmacology & Biological Psychiatry xxx (2014) xxx–xxx

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Progress in Neuro-Psychopharmacology & BiologicalPsychiatry

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Editorial

Drugs of abuse and psychiatric disorders: Neurobiologicaland clinical aspects

Individuals suffering from psychiatric disorders such as post-traumatic stress disorder, mood disorders, schizophrenia, attentiondeficit hyperactivity disorder, antisocial andborderline personality disor-ders are particularly vulnerable to drug abuse and addiction. Comparedto the general population, the prevalence of substance use disorders issignificantly elevated in these psychiatric populations (Grant et al.,2004; Hasin et al., 2007; Regier et al., 1990; Swendsen et al., 2010).This state, where a psychiatric disorder co-exists with pathological drugseeking and taking behaviour is known as co-morbidity. Co-morbidityhas major health implications and represents an important therapeuticchallenge. Across psychiatric disorders, addiction is associated withworsening of symptoms, non-compliance, suicidal ideation, violence,legal problems, unemployment, homelessness as well as health prob-lems, such as HIV and hepatitis C (Bornovalova et al., 2005; McCarthyand Petrakis, 2010; Pettinati et al., 2013; Pickard and Fazel, 2013;Willens and Morrison, 2011; Ziedonis et al., 2005). In May of 2013, theCentral Nervous System Research Group (Groupe de recherche sur lesystème nerveux central) of the Université de Montréal, Canada held aninternational symposium on the issue of addiction and psychiatric disor-der co-morbidity. This special issue presents the proceedings from thisspecial symposium. The articles presented here bring forth some of thelatest research on the clinical aspects, the neurobiological substratesand the treatment of drug addiction as a disorder and its co-morbiditywith other psychiatric disorders. A number of the articles included herereview findings derived from studying afflicted individuals. This iscomplementedby articles reporting on pre-clinical studieswhere labora-tory animals are subjected to environmental, genetic or pharmacologicalmanipulations that model specific aspects of the relationship betweendrugs and psychiatric disorders.

A first series of articles focuses on changes in reward neurocircuitrythat are potentially linked to addiction-relevant phenomena. Payer et al.(2013-this issue) present recent findings that might shed new light onthe contributions of the dopamine D3 receptor to the addiction process.The D3 receptor is principally found in the subcortical areas that consti-tute the brain's reward circuitry. Amongst all the dopamine receptorsub-types, the D3 receptor has the highest affinity for endogenous do-pamine, suggesting that slight perturbations in dopamine concentrationare likely to first affect D3 receptor-mediated behaviours. These behav-iours include the operant pursuit of appetitive stimuli, including drugsof abuse. Payer et al. (2013-this issue) review evidence from animalmodels suggesting that attenuating D3 receptor-mediated decreasesaddiction-relevant behaviours. The authors then present new humanimaging work suggesting that, just as is seen in animal models, D3 re-ceptor upregulation could be a general feature of addiction topsychostimulant drugs like cocaine and methamphetamine. The chal-lenge now is to determine whether D3 receptor upregulation could be

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Please cite this article as: Samaha A-N, Potvin S, Drugs of abuse and psyPsychopharmacol Biol Psychiatry (2014), http://dx.doi.org/10.1016/j.pnpb

a biomarker for stimulant addiction and whether manipulating D3 re-ceptor function could be a viable treatment strategy in addicts. Dopa-mine and its receptors play a central role in reward processing, andmanipulations that alter dopamine function also alter the response todrugs of abuse. Samaha (2013-this issue) presents work from animalmodels that could help us better understand how prolonged treatmentwith antipsychoticmedicationsmight impact reward function. Antipsy-chotic medications are used to manage the symptoms of schizophreniaand related psychiatric disorders. All currently used antipsychotic com-pounds interact with dopamine D2/3 receptors. Not long after thediscovery of antipsychotics, it was also discovered that prolongedtreatment with these medications can induce a state of supersensi-tivity to dopamine stimulation. Until recently, studies on the func-tional significance of this dopamine supersensitivity were limitedto effects on motor behaviour. However, Samaha reviews new workin animals showing that currently used antipsychotic treatment strate-gies can induce supersensitivity within the brain's dopamine systems,and that this in turn augments the incentivemotivational and rewardingproperties of drugs and reward cues. At the neurobiological level, theseeffects are linked to enhanced dopamine-mediated signalling at thepost-synaptic level, particularly via the dopamine D2 receptor. Thesefindings suggest that antipsychotic treatment can evoke changes inthe brain that contribute to compulsive drug seeking and drug takingbehaviours in vulnerable schizophrenia patients.

Oleson et al. (2013-this issue) and Lupica andWang (this issue) drawattention to the close interactions between the dopamine and endocan-nabinoid systems. They describe howdopamine-endocannabinoid inter-actions might influence phenomena including conditioned drugwithdrawal and drug-evoked changes in reward expectancy. Dopamineneurons within the ventral midbrain fire in bursts when individualsencounter unexpected reward or when reward is expected but notdelivered. Under these conditions, the burst firing of dopamineneurons is thought to shape behaviour such that the probability ofcoming into contact with rewards is optimised. Lupica and Wangdiscuss new work suggesting that within the ventral midbrain,endocannabinoids modulate the firing activity of local dopamineneurons and that this might modulate behaviour in response to reward,including drug reward. Oleson et al. (2013-this issue) discuss an often-ignored function of dopamine — the regulation of behaviour motivatedby aversive stimuli or states. In the addict, cues predictive of aversivewithdrawal symptoms can trigger craving and relapse to drug seekingduring abstinence. Oleson et al. present findings from animal modelssuggesting that subsecond phasic dopamine release within the ventralmidbrain encode conditioned cues during behaviours driven by negativereinforcement. These dopamine release events could be involved in con-ditioned withdrawal and its ability to trigger drug-seeking behaviour.

chiatric disorders: Neurobiological and clinical aspects, Prog Neuro-p.2014.03.012

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Importantly, the endocannabinoid system modulates subsecond dopa-mine release events, thus providing new molecular targets to attenuatedrug craving and relapse associated with conditioned withdrawal.Ghazzaoui and Abi-Dargham (2013-this issue) bring to attention thefact that interactions between cannabinoids and the dopamine systemare complex and deserving of further study. The authors review findingsfrom human imaging studies suggesting that cannabis abuse or depen-dence does not appear to be linked to dopamine alterations similar tothose documented for other drug addictions.While enhanced striatal do-pamine neurotransmissionmight be involved in the acute effects of can-nabis, it likely does not contribute in an appreciable way to theneurochemical changes thought to underlie drug addiction. This is a por-trait far different from that which has emerged for other drugs of abuselike cocaine, heroin, amphetamine or alcohol.

Chronic cannabis use is thought to increase the risk of developingpsychosis and psychotic disorders such as schizophrenia. A second se-ries of articles in this issue examines how environmental and geneticvariables mediate this effect. O'Tuathaigh et al., (2013-this issue) andRubino and Parolaro (2013-this issue) examine the contributions ofgenetic disposition and cannabis use during adolescence to the subse-quent development of psychosis and related disorders. O'Tuathaighet al. review evidence suggesting that genes encoding proteins that reg-ulate dopamine signalling or the development of dopamine neuronssuch as catechol-O-methyltransferase (COMT), AKT1 and brain-derived neurotrophic factor (BDNF) modulate the cannabis-psychosislink, and the authors provide a discussion of the neuronal basis ofthese relationships. Several lines of evidence suggest that repeated can-nabis use during adolescence is linked to an increased risk of later devel-oping psychotic symptoms. Rubino and Parolaro present evidence fromanimal models suggesting that this might occur in part because canna-bis use during adolescence compromises the normal maturation of theendocannabinoid system. This is hypothesised to result in altered con-nectivity in specific networks of the adult brain (particularly inhippocampal-related circuitry) similar to that seen in patients sufferingfrom schizophrenia. Huizink (2013-this issue) further elaborates on thelong-term risks of early exposure to cannabis, with a focus on in uteroexposure. Much attention has been paid to the long-lasting effects ofin utero exposure to tobacco and alcohol. The effects of in utero cannabisexposure have attracted less attention, in spite of the fact that cannabisis the most commonly used illicit drug during pregnancy. Huizink pre-sents evidence from her own prospective longitudinal human studiesaswell as from other studies documenting the effects of prenatal canna-bis exposure on outcome measures including behaviour and cognitivedevelopment at the neonatal, infant and childhood stages. This worksuggests that in utero exposure to cannabis likely leads to lower weightat birth, but that longer-lasting deficits in other domains of develop-ment are more difficult to establish. Huizing also summarises work onthis issue carried out in laboratory animals. Controlled preclinicalstudies show that in utero exposure to cannabinoids alters foetal devel-opment and functional outcomes in the domains of memory, motor ac-tivity, short-term learning capacity and emotional reactivity. At themechanistic level, the long-term effects of prenatal cannabis exposurecould result from changes to the normalmaturation of the brain, includ-ing alterations to dopamine and endocannabinoid networks.

Given the established links between cannabis use and the risk of de-veloping schizophrenia, howmight the endocannabinoid system be in-volved in the pathophysiology of schizophrenia? Bossong et al. addressthis important question in the present issue. The authors present evi-dence that acute exposure to cannabis or THC alters cognitive processesthat are relevant to schizophrenia including memory, emotional pro-cessing of fearful stimuli, response inhibition and high level cognitivefunctions needed for goal-directed behaviour. The authors suggestthat these effects of cannabinoids on cognitive brain function could berelated to a disruption of endocannabinoid-mediated regulation of syn-aptic transmission, leading to synaptic inefficiency in key brain regionsknown to be impaired in schizophrenia.

Please cite this article as: Samaha A-N, Potvin S, Drugs of abuse and psyPsychopharmacol Biol Psychiatry (2014), http://dx.doi.org/10.1016/j.pnpb

In addition to cannabis use, tobacco ranks amongst the mostabused substances in individuals with psychiatric disorder. Twopapers in this special issue focus on the high prevalence of cigarettesmoking in attention deficit hyperactivity disorder (ADHD) and inschizophrenia. 'Kollins and Adcock (2014-this issue) discusses thecomplex relationship between altered dopamine function, rewardprocessing and the vulnerability to tobacco smoking in individualswith attention deficit hyperactivity disorder (ADHD). Althoughsome data in this area are conflicting and additional work is muchneeded, Kollins reviews findings suggesting that during taskswhere rewards are processed, individuals diagnosed with ADHDshow lower than normal levels of brain activation in certain dopamine-rich regions. The author then presents a framework to link altereddopamine-mediated reinforcement processes and the increased vulner-ability to tobacco use and addiction in ADHD. In psychiatric populations,a greater vulnerability to drug abuse and addiction could be related to al-tered reward processes but also to the ability of drugs to amelioratesome of the psychiatric symptoms. A prominent example of this is ciga-rette smoking in schizophrenia. Themajority of people with schizophre-nia smoke cigarettes and also do so more intensely than people withoutthe disorder. In this issue, Mackowick et al. present their own and otherwork demonstrating that individuals with schizophrenia derive impor-tant cognitive benefits from smoking and from other manipulationsthat increase nicotinic receptor activity. Given this reality, it appears use-ful to target the nicotine receptor system for the design and explorationof newmedications to treat cognitive deficits in schizophrenia. Althoughcigarette smoking might have some therapeutically useful effects,smoking tobacco increases the liability to several serious conditions in-cluding cancer and cardiovascular diseases. Current therapeutic ap-proaches designed to keep abstinent smokers from relapsing are oflimited efficacy. For this reason, effective translational research is neededto impel the exploration of new anti-smoking treatments. Strategies toachieve this are reviewed in the present issue by Le Foll et al. The authorshighlight the bench-to-bedside strategy that has driven the develop-ment and clinical use of inverse agonists at the cannabinoid CB1 receptoras an anti-smoking medication. Le Foll et al. then present an unconven-tional bedside-to-bench strategy that has led to the discovery that theinsula could play an important role in the addictive properties of nico-tine. The authors highlight that research that allows close interaction be-tween animal and clinical observations is critical to better understandthe neurobiology of tobacco addiction and its treatment.

Chronic drug use most often makes mental illness more severeand difficult to treat. At the same time, certain drugs—in particulartobacco—appear to ameliorate at least some psychiatric symptoms. Thearticles brought together in this special issue aim to spark discussion onseveral issues related to the co-morbidity problem, from the question ofhowdrugs including cannabis and tobacco can contribute to the aetiologyand course of certain psychiatric conditions to what factors can promoteor protect from this outcome. The hope is that a reflection on these issueswill guide new translational research on the causes and mechanisms ofdrug use in psychiatric populations. As scientists in this field, our task isto better understand the genetic, neurobiological and environmental pro-cesses linking drug abuse and mental illness. Our efforts will bear fruitonly ifwe take every occasion to disseminate our discoveries—this specialissue being a vector towards this goal. Thus, we conclude by highlightingthe need for increased collaboration between the scientistsmodelling andresearching this co-morbidity, the clinicians treating the afflicted individ-uals and themembers of the government and the publicwho shape opin-ion and funding policies on this important issue.

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Guest EditorAnne-Noël Samaha

Department of Pharmacology and CNS Research Group,Faculty of Medicine, Université de Montréal, Montreal, QC, Canada

Corresponding author at: Department of Pharmacology,Université de Montréal, C.P. 6128, Succursale Centre-ville,

Montreal, Quebec H3C 3J7, Canada.Tel.: +1 514 343 6111x32788; fax: +1 514 343 2291.

E-mail address: Anna.samaha@umontreal.ca.

Guest EditorStéphane Potvin

Department of Psychiatry, Faculty of Medicine,Université de Montréal, Montreal, QC, Canada

Available online xxxx

chiatric disorders: Neurobiological and clinical aspects, Prog Neuro-p.2014.03.012