An Endocannabinoid Hypothesis of Drug Reward and Drug Addiction

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<ul><li><p>An Endocannabinoid Hypothesis of DrugReward and Drug Addiction</p><p>Emmanuel S. Onaivi</p><p>Department of Biology, William Paterson University, Wayne, New Jersey, USA</p><p>Pharmacologic treatment of drug and alcohol dependency has largely been disappoint-ing, and new therapeutic targets and hypotheses are needed. There is accumulatingevidence indicating a central role for the previously unknown but ubiquitous endo-cannabinoid physiological control system (EPCS) in the regulation of the rewardingeffects of abused substances. Thus an endocannabinoid hypothesis of drug reward ispostulated. Endocannabinoids mediate retrograde signaling in neuronal tissues andare involved in the regulation of synaptic transmission to suppress neurotransmitterrelease by the presynaptic cannabinoid receptors (CB-Rs). This powerful modulatoryaction on synaptic transmission has significant functional implications and interactionswith the effects of abused substances. Our data, along with those from other investiga-tors, provide strong new evidence for a role for EPCSmodulation in the effects of drugsof abuse, and specifically for involvement of cannabinoid receptors in the neural basis ofaddiction. Cannabinoids and endocannabinoids appear to be involved in adding to therewarding effects of addictive substances, including, nicotine, opiates, alcohol, cocaine,and BDZs. The results suggest that the EPCS may be an important natural regulatorymechanism for drug reward and a target for the treatment of addictive disorders.</p><p>Key words: marijuana; capsaicin; endocannabinoids; cannabinoid receptors; dopa-mine; drug dependency; reward; addiction; withdrawal anxiogenesis</p><p>Introduction</p><p>In reviewing the history of human drugaddiction, one finds previous misconceptionsthat people addicted to drugs lacked willpowerand were morally weak. But we now knowthat drug addiction is a chronic relapsingbrain disease characterized by the compulsiveuse of addictive substances despite adverseconsequences to the individual and society.For more than 50 years, it has been assumedthat all drugs of abuse release dopamine in thebrains reward system to produce pleasure andeuphoria, consequently leading to addictionin vulnerable individuals.1,2 However, manyagents, such as inhalants, barbiturates, orbenzodiazepines, do not activate midbrain</p><p>Address for correspondence: Department of Biology, William PatersonUniversity, 300 PomptonRoad,Wayne,NJ 07470. Voice:+973-720-3453;fax: +973-720-2338.</p><p>dopamine-mediated transmission consistently,despite the fact that these drugs have rewardingproperties and are heavily abused.1 Thereforedopamine is not a simple marker of reward orhedonia and it might no longer be tenable tosuggest that drugs of abuse are simply activatingthe brains natural reward system.2 In thisarticle I propose that the dopamine hypothesisis another misconception. The dopamineprojections in the brain do not convey a spe-cific reward signal since dopamine releaseoccurs as a response not only to all drugsof abuse, but also to stress, foot shock, andaversive and salient stimuli.3,4 Mice thatcannot make dopamine (DD mice) have beenused to test the hypothesis that dopamine isnecessary for reward. The results show thatdopamine is not required for natural reward5</p><p>and morphine-induced reward.6 Thus, nu-merous problems are associated with thedopamine hypothesis of reward (Table 1). For</p><p>Ann. N.Y. Acad. Sci. 1139: 412421 (2008). C 2008 New York Academy of Sciences.doi: 10.1196/annals.1432.056 412</p></li><li><p>Onaivi: Endocannabinoids in Addiction 413</p><p>TABLE 1. Problems Associated with Dopamine Hypothesis of Reward: Beyond the Nucleus Accumbensand Dopamine Hypothesis of Reward</p><p> Not all studies point to a unitary role for dopamine in one brain circuit as the most relevant system in drug abuse. Dopamine may not be involved in brain reward mechanisms, as was previously thought. Reward centers in the brain consist of multiple systems and neuroanatomic sites other than the mesoaccumbensdopamine circuitry.</p><p> Dopamine-independent mechanisms involving other neurotransmitters like glutamate, GABA, serotonin,endocannabinoids, stress hormones, and dynorphin are potential substrates for the rewarding effects of abusedsubstances.</p><p> In schizophrenics, dopamine excess in mesoaccumbens causes heightened state of arousal but not pleasure. Smokers and cocaine addicts continue to take hits long after the cigarettes become distasteful or after the effectsof cocaine have worn off.</p><p> Addictions arise from a complex pattern of pathogenetic and environmental situations. Differential effects of abused substances on the complex network of genes, hormones, neurotransmitters, andmodulators do not support the concept of a single reward transmitter.</p><p> Manipulation of dopamine circuitry as a pharmacologic target should provide medication for substance abuse. There is no causal relationship with regard to dopamine as a pleasure or reward transmitter triggered by abusedsubstances.</p><p> Activation of dopamine pathways is not involved in brain-stimulation reward of all brain sites relevant toaddiction.</p><p> Electrolytic lesions and 6-OH dopamine lesion studies of dopamine cell bodies in the ventral tegmental area andother brain sites did not attenuate brain-stimulation reward.</p><p>example, self-administration of opiates andalcohol occurs even when the mesolimbicdopamine system is lesioned7 and interferencewith accumbens dopamine transmission doesnot substantially blunt the primary motivationfor natural rewards.2 Although we cannot un-derestimate the role of dopamine in the centralnervous system, recent studies in schizophre-nia, for which the dopamine hypothesis hasdominated treatment approaches, now showsthat the glutamate receptor offers promise fora new class of anti-psychotic agents (see 2007report in Nature Medicine at .)</p><p>The activation of the natural reward sys-tem, supposedly mediated by the accumbensdopamine, cannot reasonably be used as a gen-eral explanation for drug abuse and addiction.2</p><p>It is timely that there is accumulating evidenceindicating a central role for the endocannabi-noid physiological control system (EPCS) in theregulation of the rewarding effects of abusedsubstances. Such recent studies have shown thatthis endocannabinoid system is involved in thecommon neurobiological mechanism underly-</p><p>ing drug addiction912 (Table 2). Therefore,an endocannabinoid hypothesis of drug re-ward is postulated from data from our stud-ies and those of others. Endocannabinoids me-diate retrograde signaling in neuronal tissuesand are involved in the regulation of synaptictransmission to suppress neurotransmitter re-lease by the presynaptic cannabinoid receptors(CB-Rs). This powerful modulatory action onsynaptic transmission has significant functionalimplications and interactions with the effects ofabused substances. Additional support for theendocannabinoid hypothesis of drug reward isderived from an action of cannabinoids or mar-ijuana use on brain reward pathways that issimilar to that of other abused substances. Fur-thermore, administration of cannabinoids orthe use of marijuana exert numerous pharma-cologic effects through their interactions withvarious neurotransmitters and neuromodula-tors (Table 2). In our preliminary studies test-ing the endocannabinoid hypothesis of drug re-ward, we investigated the interaction betweenvanilloid and cannabinoid agonists and an-tagonists in the mouse model of aversion us-ing the elevated plus-maze test. The vanilloid</p></li><li><p>414 Annals of the New York Academy of Sciences</p><p>TABLE 2. Framework for an Endocannabinoid Hypothesis of Drug Reward</p><p> An endocannabinoid physiological system control system (EPCS) exists and has a central role in the regulationof the rewarding effects of abused substances.</p><p> The EPCS is intricately involved in almost all the biological processes of the human body and brain. The EPCS appears to exert a powerful modulatory action on retrograde signaling associated with cannabinoidinhibition of synaptic transmission.</p><p> The retrograde signaling appears to be involved in the modulation of neurotransmitter release by cannabinoidsand endocannabinoids.</p><p> The abundant distribution of the cannabinoid receptors in the brain provides the EPCS with limitless signalingcapabilities of crosstalk within, and possibly between, receptor families.</p><p> A missense mutation in human fatty acid amide hydrolase may be associated with problem drug use invulnerable individuals.</p><p> Cannabinoids induce alterations in brain disposition and pharmacologic actions of drugs of abuse. There are changes in endocannabinoid contents in the brain of rats chronically exposed to nicotine, ethanol, orcocaine.</p><p> Runners high, the sense of euphoric well-being that come with vigorous exercise, stimulates the release andelevated levels of endocannabinoids</p><p> The mechanisms of dependence on different substances appear to be different in terms of their impact on theEPCS.</p><p> The endocannabinoid transmission is a component of the brain reward system and appears to play a role independence/withdrawal of abused substances.</p><p> CB1 knockout mice have a reduced sensitivity to reward. However, mice that cannot make dopamine (micelacking tyrosine hydroxylase) respond to rewarding stimuli, indicating reward without dopamine.</p><p> Overeating, alcohol, and sucrose consumption is decreased in CB1 receptordeleted mice. The endocannabinoid system is involved in the neural circuitry regulating alcohol consumption and motivationto consume alcohol.</p><p> Evidence for the existence of a functional link between the cannabinoid and opioid receptor systems in thecontrol of alcohol intake and motivation to consume alcohol.</p><p> Alcohol self-administration is decreased and alcohol sensitivity and withdrawal in CB1 receptor knockout miceis increased.</p><p> The endocannabinoid system modulates opioid rewarding and addictive effects by crosstalk betweenendogenous opioid and endocannabinoid systems.</p><p> Involvement of endocannabinoid and glutamate neurotransmission in brain circuits is linked to reward andmnemonic processes. Long-term potentiation (LTP) is abolished in mice lacking mGluR5 receptors andenhanced LTP and memory in mice lacking cannabinoid CB1 receptors.</p><p> Memory-related plasticity may be a common mechanism in the endocannabinoid system in the control bycannabinoids of conditioned drug seeking.</p><p>agonist used is a natural product, capsaicin, theactive ingredient in hot chili peppers, whichis known to be habit forming. In a follow-upstudy, we determined the effect of the CB1 an-tagonist, rimonabant, on withdrawal aversionsfrom chronic treatment with abused drugs.Our results suggest that the endocannabi-noid physiological control system may be animportant natural regulatory mechanism forreward.</p><p>Endocannabinoid Physiological ControlSystem and Reward, Drug Abuse,</p><p>and Addictions</p><p>Many studies now show that the endo-cannabinoid system13,14 is involved as themajor player and most likely common neu-robiological mechanism underlying drug re-ward. There is substantial evidence supportinga role for the endocannabinoid system as</p></li><li><p>Onaivi: Endocannabinoids in Addiction 415</p><p>a modulator of dopaminergic activity in thebasal ganglia.15 The endocannabinoid sys-tem therefore participates in the primaryrewarding effects of alcohol, opioids, nico-tine, cocaine, amphetamine, cannabinoids, andbenzodiazepines through the release of endo-cannabinoids that act as retrograde messen-gers to inhibit classical transmitters, includ-ing dopamine, serotonin, GABA, glutamate,acetylcholine, and norepinephrine.13 Further-more the endocannabinoid system is intricatelyinvolved in the common mechanisms underly-ing relapse to drug-seeking behavior by medi-ating the motivational effects of drug-relatedenvironmental stimuli and drug re-exposure.11</p><p>Therefore substantial data now point to a rolefor the endocannabinoid system in trigger-ing and/or preventing reinstatement of drug-seeking behavior.12 It appears that the effectsof perturbation of the endocannabinoid sys-tem by drugs of abuse can be ameliorated byrestoring the perturbed system using cannabi-noid ligands. It is not surprising that prelimi-nary studies with cannabinoid antagonists areshowing promise in the reduction of drug use,in smoking cessation, and reduction in alco-hol consumption, and rimonabant has been ap-proved inEurope for treating obesity. It is hopedthat these encouraging positive results will leadto new therapeutic agents in the treatment ofdrug dependency. The promiscuous action anddistribution of cannabinoid receptors in mostrelevant biological systems provide the EPCSwith limitless signaling capabilities for crosstalkwithin, and possibly between, receptor fami-lies, which may explain the myriad behavioraleffects associated with smokingmarijuana. TheEPCS therefore appears to play a central rolein regulating the neural substrate underlyingmany aspects of drug addiction, including crav-ing and relapse.8 The findings that the EPCS isinvolved in the reinstatement model providedevidence of the EPCS in the neural machineryunderlying relapse. Relapse, the resumption ofdrug taking after a period of drug abstinence, isconsidered themain hurdle in treating drug ad-</p><p>diction and pharmacologic modulation of theendocannabinoid tone with rimonabant gavepositive results in human trials. A summaryof data from recent studies of the efficacies ofcannabinoid antagonist in mutant mice has re-cently been reviewed.10 As the usefulness of thepharmacotherapy of substance abuse has beenlimited, there is now sufficient preclinical evi-dence for clinical trials to evaluate the efficacyof cannabinoid-based drugs in the treatment ofdrug dependency.</p><p>Interaction between CB1 and CB2Receptors in Drug Abuse</p><p>and Addiction</p><p>The expression of CB1 cannabinoid recep-tors (CB1-Rs) in the brain and its periphery hasbeen well studied, but the brain neuronal ex-pression of CB2-Rs had been ambiguous andcontroversial and its role in substance abuse isunknown. There is now ample evidence for thefunctional presence of CB2-Rs in mammalianbrain neurons.1618 We have investigated theinvolvement of CB2-Rs in alcohol preferencein mice and alcoholism in humans.19 So we at-tempted to determine whether CB2-Rs in thebrain play a role in alcohol abuse/dependencein an animal model and then examined an as-sociation between theCB2 gene polymorphismand alcoholism in Japanese population. Thereis an association between the Q63R polymor-phism of the CB2 gene and alcoholism in theJapanese population. Our data therefore re-vealed that CB2-Rs are functionally expressedin brain neurons and play a role in substanceabuse and dependency.1719 Now that we knowthat CB2-Rs are present in the brain, the nextquestion is: what is the nature of and con-tribution to the known effects of CB1-Rs inthe rewarding effects of drug abuse? In viewof the recent definitive demonstration of neu-ronal CB2-Rs in brain, one possible explana-tion may be that CB2-Rs and CB1-Rs workindependently and/or cooperatively in differ-ent neuronal populations to reg...</p></li></ul>


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