Endocannabinoid regulation of relapse mechanisms

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  • Pharmacological Research 56 (2007) 418427

    Review

    Endocannabinoid regulation of reLiana Fattore a,b,, Paola Fadda b,c, W

    Abstract

    Addictionstate of withoutcome offor the treatproviding athat reinstatenot blockedinvolvementactivation while blockade of such receptors may prevent reinstatement of place conditioning induced by either drug primings or drug-associatedcues. Finally, biochemical studies evaluating changes in endocannabinoid levels, CB1 receptor density and CB1 mRNA expression during re-exposure to drug following extinction are also examined. Taken together, the evidence available has important implications in the understandingand treatment of relapsing episodes in patients undergoing detoxification. 2007 Elsevier Ltd. All rights reserved.

    Keywords: C

    Contents

    1. Introd2. Self-a3. Cond4. Chan5. Discu

    Refer

    1. Introdu

    Drug adcompulsiveConsistentlreported th

    CorresponNeuroscienceCagliari, Italy

    E-mail ad

    1043-6618/$doi:10.1016/jB1 receptor; Reinstatement; Self-administration; Conditioned place preference; Addiction

    uction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 418dministration studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419itioned place preference studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421ges in endocannabinoid contents, CB1 receptor density and function, and mRNA levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421ssion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423ences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424

    ction

    diction is defined in behavioural terms as craving,drug use and relapse or recurrent use of substances.

    y high relapse rates (7590%) which have beenroughout the literature for a variety of compulsive

    ding author at: CNR Institute of Neuroscience c/o Department of, Cittadella Universitaria, 09042 Monserrato (CA), University of. Tel.: +39 070 6754327; fax: +39 070 6754312.dress: lfattore@in.cnr.it (L. Fattore).

    behaviours, such as gambling [1,2], binge eating [3,4], and drugaddiction [5], support the conceptualization of addiction as afamily of social problem behaviours which share essential simi-larities. To date, pharmacologic approaches have been less thanpromising in preventing relapse, with only a few exceptionsof patients with long histories of heroin use and subsequentrehabilitation on a maintenance program or highly motivatedsmokers. Indeed, although smoking cessation rates have contin-ued to increase, the vast majority of smokers who quit eventuallyrelapse. Typically, available medications may be corrective butnot curative for severely addicted persons, as the majority expe-

    see front matter 2007 Elsevier Ltd. All rights reserved..phrs.2007.09.004a Institute of Neuroscience, CNR, National Research Council, Italyb Centre of Excellence Neurobiology of Addiction, Italy

    c Department of Neuroscience, University of Cagliari, ItalyAccepted 5 September 2007

    involves a complex neuropharmacologic behavioural cycle, in which positive reinforcement exerted by the drug and the negativedrawal drive the user to extremes to obtain the drug. Comprehensive studies have established that relapse is the most common

    recovery programs treating addictive behaviours. Several types of anticraving medication are available nowadays, such as naltrexonement of alcoholism, bupropion for nicotine, methadone or buprenorphine for heroin. This review focuses on recent behavioural datarationale for an endocannabinoid mechanism underlying reinstatement of compulsive drug seeking. Studies supporting the contentionment of extinguished drug self-administration behaviour may be generated by cannabinoid CB1 receptor agonists and attenuated, if

    , by CB1 receptor antagonists, are here reviewed. In support to these findings, conditioned place preference studies substantiate theof the endocannabinoid system in recidivism mechanisms by demonstrating that motivation to relapse can be triggered by CB1 receptorlapse mechanismsalter Fratta a,b,c

  • L. Fattore et al. / Pharmacological Research 56 (2007) 418427 419

    rience a return of symptoms after withdrawal of maintenancetreatment.

    An estaeffects of awhich drugresponse: finjection ismodel humhave been mlishment ofollowed bfrequency,quency of t[7]. Advanctified condthe three ming to theelements caddiction [eliciting drresemblesthus confirmenduring afollowing waptive procin mechaniappearancedepression

    Consideendocannaaffective stprotein-couof the braresponses,ingly, the eemotional[10,11], oracting as rglutamatermodulatorying with thnoid recepnervous sy

    Recentlnoid signadrug seekinperiod of dusing pre-ccannabinoiseeking epivenous drumodel in thpreferencetion. Theseassess the pbeen appliecraving and

    While summarizing behavioural studies evaluating the effectsof selective CB1 receptor agonists, CB1 antagonists and fatty

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    eekinncesmpheh reby muentfounblished method applied in study of the reinforcingdrug entails the use of experimental animal models inacquisition is contingent upon a specific behaviouralor example, an animal will soon learn that a druggiven every time it presses a particular lever [6]. Toan relapse in laboratory animals, similar protocolsodified in reinstatement procedures, where estab-

    f responding is maintained by drug reinforcer andy its extinction. Once the behaviour has decreased inexperimental manipulations are imposed and the fre-he previously reinforced behaviour is then reassesseding knowledge in the field of neuroscience have iden-

    itioned cueing, drug priming and stress exposure asain types of stimuli capable of eliciting relapse, point-learned responses to drug-related stimuli as criticalontributing towards the chronic relapsing nature of8]. The long-lasting value of contextual stimuli inug seeking behaviour in animal models of relapsethe survival of conditioned cue reactivity in humans,

    ing the pivotal part played by learning factors in theddictive potential of drugs. Vulnerability to relapse

    ithdrawal is proposed to be the result of neuroad-esses within the brain which lead to impairmentsms mediating hedonic perception of the drug andof affective changes such as dysphoria, anxiety andduring withdrawal.rable evidence exists implicating perturbations inbinoid signalling as potential substrates for theseates. Cannabinoid receptors belong to a family of G-pled receptors and are densely distributed in areas

    in related to motor control, cognition, emotionalmotivated behaviour and homeostasis [9]. Accord-ndocannabinoid system can be modulated to enhancelearning, such as extinction of conditioned fearto ameliorate anxiety and depression [12,13]. By

    etrograde signalling messengers in GABAergic andgic synapses, endocannabinoids are likely to exert a

    control of post-synaptic transmission, thus interact-e majority of brain neurotransmitters [14]. Cannabi-tors are also critical modulators of the autonomicstem, the immune system and microcirculation.y, pre-clinical studies have shown how endocannabi-lling is crucially implicated in the re-initiation ofg and taking behaviours following even a prolongedrug abstinence. Here, we review data from studieslinical models in rats and mice on the effects of

    d system manipulation on the re-occurrence of drugsodes following extinction, as measured by the intra-g self-administration protocol, the most widely usede study of addictive behaviour, and conditioned placeprocedure, a behavioural model of incentive motiva-two methodologies have been used traditionally toositive reinforcing properties of a drug, but have alsod in examining brain reward mechanisms, includingrelapse.

    acid amconditcellulanoid sbroaderesearc

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    tion of0.5 mgin lonstable55,212CB1 reHU 25Listertion [2prevenrimonaing peprocesies demmodulrefs. [in relasystemdrug-ssubstametha

    Wituatedsubseqit washydrolase inhibitors on extinguished responding org, we will also examine recent works investigatingmolecular mechanisms by which the endocannabi-may impinge on relapsing neural circuitry. The

    plications of the data reviewed here for futured for the maintenance of addicted patients underon are briefly discussed.

    ministration studies

    lf-administration (SA) paradigms have long beenas a tool in exploring behavioural and neuroanatom-

    s of addiction, providing essential information onty factors and brain circuits involved in drug abuseence [15]. Both acute SA paradigm in drug-nave

    hronic SA in trained rats have been used in the pastthe rewarding properties of synthetic cannabinoidss subsequently confirmed for THC and endo-ds in tra