Endocannabinoid regulation of relapse mechanisms

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Pharmacological Research 56 (2007) 418427ReviewEndocannabinoid regulation of reLiana Fattore a,b,, Paola Fadda b,c, WAbstractAddictionstate 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: CContents1. Introd2. Self-a3. Cond4. Chan5. DiscuRefer1. IntroduDrug adcompulsiveConsistentlreported th CorresponNeuroscienceCagliari, ItalyE-mail ad1043-6618/$doi:10.1016/jB1 receptor; Reinstatement; Self-administration; Conditioned place preference; Addictionuction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 418dministration studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419itioned place preference studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421ges in endocannabinoid contents, CB1 receptor density and function, and mRNA levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421ssion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423ences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424ctiondiction 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 compulsiveding 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, Italyc Department of Neuroscience, University of Cagliari, ItalyAccepted 5 September 2007involves 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 commonrecovery 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,cL. Fattore et al. / Pharmacological Research 56 (2007) 418427 419rience 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 mechaniappearancedepressionConsideendocannaaffective stprotein-couof the braresponses,ingly, the eemotional[10,11], oracting as rglutamatermodulatorying with thnoid recepnervous syRecentlnoid signadrug seekinperiod of dusing pre-ccannabinoiseeking epivenous drumodel in thpreferencetion. Theseassess the pbeen appliecraving andWhile summarizing behavioural studies evaluating the effectsof selective CB1 receptor agonists, CB1 antagonists and fattyideioninr andystemr imh anficatif-adg seusedatureabilipendnd close], ainoitionsl modunderebtes ir thehavely arelapgente ina CBkgg-absSA-2 (cept0 (2Hoo6,27tedbanr se,ses [onsates25,2psehaseekinncesmpheh 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 relapseithdrawal 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 areasin 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]. Byetrograde signalling messengers in GABAergic andgic synapses, endocannabinoids are likely to exert acontrol 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 ofd 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 sbroaderesearcdetoxi2. SelDruwidelyical fevulnerand demice ato disc[1618cannabadaptaanimaanisms[8], thsubstraOvetoriesnot onencesa morean acution of0.5 mgin lonstable55,212CB1 reHU 25Listertion [2prevenrimonaing peprocesies demmodulrefs. [in relasystemdrug-ssubstamethaWituatedsubseqit washydrolase inhibitors on extinguished responding org, we will also examine recent works investigatingmolecular mechanisms by which the endocannabi-may impinge on relapsing neural circuitry. Theplications of the data reviewed here for futured for the maintenance of addicted patients underon are briefly discussed.ministration studieslf-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-navehronic SA in trained rats have been used in the pastthe rewarding properties of synthetic cannabinoidss subsequently confirmed for THC and endo-ds in trained squirrel monkeys [19,20]. Importantly,of these paradigms to extinction/reinstatementels of relapse have allowed investigation of the mech-erlying resumption of drug use in abstinent subjectsy increasing our knowledge of the neuroanatomicalnvolved in relapse [2123].past decade, data collected in our and other labora-demonstrated that stimulation of the CB1 receptorsffects relapse to cannabinoids [24], but also influ-se to other drugs of abuse (i.e. heroin), thus exertingeral control on drug seeking behaviour [25]. Indeed,traperitoneal (i.p.) or subcutaneous (s.c.) administra-1 receptor agonist, such as WIN 55,212-2 (0.25 and1), triggers relapse to cannabinoid seeking behaviourtinent Long Evans rats with a previous history of[24]. Likewise, CB1 receptor stimulation by WIN0.15 and 0.3 mg kg1 i.p.) as well as by two otheror agonists CP 55,940 (0.05 and 0.1 mg kg1 i.p.) and0g kg1 s.c.) elicits relapse to heroin in abstinentded or Wistar rats following 3 weeks of extinc-]. Importantly, cannabinoid-induced reinstatement isby pre-treatment with the CB1 receptor antagonistt, at doses (0.33.0 mg kg1) not affecting respond-thus demonstrating to be CB1 receptor-mediated24,26,28]. These findings extended previous stud-trating how endocannabinoid transmission cruciallythe reinforcing properties of opioids (reviewed in931]). However, besides its well established roleto cannabinoids and opioids, the endocannabinoidbeen reported to be implicated in craving for andg resumption of many other widely used addictive, both legal (alcohol, nicotine) and illegal (cocaine,tamine).spect to alcohol abuse, when drug intake was eval-eans of a two-bottle free-choice paradigm afterperiod of alcoholization and alcohol deprivation,d that rimonabant (0.33.0 mg kg1 i.p.) prevented420 L. Fattore et al. / Pharmacological Research 56 (2007) 418427the acquisition of alcohol drinking behaviour and decreasedvoluntary ethanol intake in Sardinian alcohol-preferring (sP)rats geneticdecreases vintake [34,preferencethe controlalcohol) anMore reinteractioni.p.) was soperant realso responevidence onoid primilong-lastinexposed toa persistenweeks. Inrary (12 dnon-continhol deprivaNotably, uevaluatingvation effeconsumptiohas been ploss of conin human asuch an eftreatment wor 0.33.0tor antagonrimonabanin reducingorange extrpresentatiowhile not afHowever, tand 10.0 mseeking trigBehaviohave also bdemonstratto block ninucleus accbut not subnicotine disreceptor anunder bothviding furthbetween thtive behavi(CB1 knocthat of theithat integrifor the expIn the past years, relapse studies focussed mainly on heroinor cocaine seeking reinstatement and, to a lesser extent, to alco-kingereas shour eus seuishencee-reockatenuanicohenigencemgedablistodiesticipex.0 meDte p0.1 mtar re-prinhibat 0.s wnist]. In3.0epenent [ine.as no-2-trtionally,1 rectotaketionae reinandR-(+epenhilecantlre reystebanof emuluthisally selected for alcohol preference [32,33]. It alsooluntary consumption of ethanol along with sucrose35] and water consumption without altering alcohol[36], pointing to an endocannabinoid mechanism inof operant behaviour motivated by both drug (i.e.d natural rewards (i.e. sucrose).cently, it has been found that alcoholcannabinoids extended to relapse processes, as THC (1.0 mg kg1hown to significantly reinstate in trained animalssponding previously reinforced with alcohol, butding reinforced by beer or sucrose [37], providingf a relatively non-specific effect of the cannabi-ng. Moreover, CB1 receptor stimulation produces ag increase of the alcohol deprivation effect, as ratsWIN 55,212-2 during alcohol deprivation showedt increase in responding for alcohol lasting over 2contrast, control animals only displayed a tempo-ays) increase in alcohol consumption, suggesting thatgent chronic exposure to cannabinoids during alco-tion may potentiate relapse into alcohol use [38].nanimous consensus has been reached by studiesthe effect of CB1 receptor blockade on alcohol depri-ct, i.e. the temporary increase in voluntary alcoholn occurring following a period of abstinence, whichroposed to resemble increased alcohol intake withtrol over drinking frequently associated with relapselcoholics [39]. In fact, a complete abolishment offect in sP rats has been described following pre-ith either 0.33.0 mg kg1 i.p. of rimonabant [40]mg kg1 i.p. of the newly synthesized CB1 recep-ist, SR147778 [41]. In line with these observations,t (0.33.0 mg kg1 i.p.) has proved to be effectivereinstatement of alcohol seeking triggered by anact odour previously associated with the contingentn of the drug, i.e. a drug-associated cue [35,42],fecting foot-shock stress-induced reinstatement [43].he anandamide transport inhibitor AM404 (0.4, 2.0g kg1 i.p.) fails to modify reinstatement of alcoholgered by a drug-associated cue [44].ural interactions between cannabinoids and nicotineeen proposed by several independent investigations,ing that rimonabant (0.33.0 mg kg1 i.p.) is ablecotine-induced dopamine release in the shell of theumbens, reduce nicotine intake in an SA procedurestitute for nicotine or antagonize the nicotine cue in acrimination procedure [45]. In turn, the 7 nicotinictagonist methyllycaconitine reduced cannabinoid SAFR1 and FR5 schedules of reinforcement [46], pro-er support to the existence of a functional cross-talke CB1 and nicotinic receptors in modulating addic-our. On the other hand, mice lacking the CB1 receptorkout) do self-administer nicotine at a level similar tor corresponding wild type littermate [47], suggestingty of CB1 receptors is not an essential prerequisiteression of nicotine reinforcing effects.hol seeunanswi.p.) wbehavistimulextingabstinenicotinthat bli.p.) ateitherstrengta morereinforprolonEstrelapselier stuits parlowing(0.33Spraguan acu(0.02in Wiscocainto be ieither[52], aantagoi.p. [532 (0.3dose-dstatemto cocai.p.) w55,212resumpFinof CBrelapsedrug ina funcand thboth aloguedose-drats, wsignifiMonoid srimonaeffectsto a stiAs in, thus leaving many issues related to nicotine relapsed. Only a few years ago, rimonabant (1.0 mg kg1own to attenuate the reinstatement of nicotine seekingvoked by non-contingent exposure to a drug-pairedveral weeks after responding for nicotine had beend [48], thus proving to be of help in maintainingfrom nicotine by diminishing the reinforcing value oflated stimulus. Accordingly, a second study showedde of CB1 receptors by rimonabant (1.03.0 mg kg1ted responding for stimuli previously associated withtine or sucrose delivery in a similar fashion [49],ng the hypothesis that endocannabinoids may playeral role in modulating cue reactivity or conditionedent of both drug and natural reinforcers even afterabstinence.hment of a role of the endocannabinoid system incocaine has been reached only recently, as ear-using a within-session protocol seemed to excludeation in the reinitiating of cocaine seeking fol-tinction. Indeed, although a priming with THCg kg1 i.p.) does not trigger relapse to cocaine inawley rats 3 h from the last access to the drug [50],riming with the more potent CB1 agonist HU210g kg1 s.c.) elicits reinstatement of cocaine-seekingats after 2 weeks of extinction [51]. Accordingly,med relapse in cocaine-trained rats has been reportedited by pre-treatment with rimonabant, administered033.0 mg kg1 s.c. [51] or at 5.010 mg kg1 i.p.ell as by the novel highly selective CB1 receptorAM251 at doses ranging from 1.0 to 10 mg kg1triguingly, subchronic treatment with WIN 55,212-mg kg1 i.p.) following interruption of cocaine SAdently attenuated cue-induced cocaine seeking rein-54], supporting a cannabinoid mechanism in relapseHowever, priming injection of cocaine (10 mg kg1t able to reinstate responding for cannabinoid in WINained rats, thus excluding a cocaine mechanism in theof cannabinoid seeking [24].relatively little is known at present about the effecteptor stimulation or blockade on the propensity tomethamphetamine (METH) following cessation of. Several years ago, a pioneering SA study revealedl interaction between the endocannabinoid systemnforcing properties of METH by demonstrating thatamide (0.12.0 mg kg1 i.p.) and its synthetic ana-)-methanandamide (1.05.0 mg kg1 i.p.) tended todently increase METH self-administration in trainedthe CB1 antagonist AM251 (1.05.0 mg kg1 i.p.)y decreased responding [55].cently, a second study showed how the endocannabi-m may also modulate relapse to METH seeking,t (3.2 mg kg1 i.p.) being able to block the reinstatingither an acute METH priming or a single re-exposures previously paired with drug infusion delivery [56].study the cyclooxigenase inhibitor diclofenac wasL. Fattore et al. / Pharmacological Research 56 (2007) 418427 421also found to attenuate cue- and drug-induced reinstatement ofMETH seeking, authors argued on the possibility that the arachi-donic acidparticipatio[56]. Howean acute ininduced reiAltogethof an endoment, althoon experimused. Notaon stress-inhol [35] sesuch as riming reinstacues predicinduced by3. ConditiConditioing is a behaffective (ptive drugs alearning [6erties of suthe primarywith a distor drug veof such ass(UCS) acquare given ais demonstin the drugenvironmement associncentive pprinciplesing which afollowing iBased on tCPP appeatiguous asswithin thiscommonlyliability ofdamentallyproved to bpropertiesunsuccessfthe aid of pA masscannabinoiimportant cvalue of seforcers. InCPP induced by cocaine [64], morphine [7477], nicotine [78],3,4 methylenedioxymethamphetamine (MDMA) [79] and thelly of Sad bypelleinoiecepndicance.foredinsta. ByB1tinebant lonminisione las2 weeffecinoiarnises.g, loidiond and 5admiatiato pive leangey anhin taltel stude (As reled ade leand to], suin thrselycant,88],dinglan Ss [9ortaue ascascade is likely to mediate endocannabinoid systemn in the reinstatement of METH seeking behaviourver, at doses ranging from 0.032 to 0.32 mg kg1,travenous priming of AM251 fails to affect METH-nstatement of METH seeking [57].er, these studies clearly demonstrate involvementcannabinoid mechanism in drug-induced reinstate-ugh discrepant results have been obtained dependingental protocol, range of drug doses or animal strainbly, CB1 receptor blockade likely produces no effectduced reinstatement of either cocaine [51] or alco-eking, sustaining the notion that CB1 antagonistsonabant may be effective in contrasting drug seek-tement elicited by drug primings or presentation oftive of drug availability, rather than preventing thata stressor (for recent reviews see refs. [58,59]).oned place preference studiesned place preference (CPP) or aversion (CPA) test-avioural method believed capable of measuring theositive, neutral or negative) properties of psychoac-nd is a commonly used measure of positive incentive0,61]. CPP is used in evaluation of motivational prop-bstances, consisting in repeated association betweenunconditioned properties of a stimulus (i.e. drug)inct environment, and a neutral stimulus (i.e. salinehicle) with a second environment. After a numberociations, during which the unconditioned stimulusires properties of conditioned stimulus (CS), animalsccess to both contexts in a drug-free state. A CPPrated if the animal spends a greater amount of time-paired environment than the saline/vehicle-pairednt. The preference demonstrates that the CS environ-iated with the drug effects has acquired conditionedroperties [62]. Place-preference learning follows theof classical conditioning, including extinction, dur-nimals display a reduced approach to the CS contextts experience in the absence of the UCS drug [63].heoretical formulations of Pavlovian conditioning,rs to reflect a preference for a context due to the con-ociation between the context and a drug stimulus:theoretical framework, it seems clear that althoughused for assessing rewarding properties and abusea drug, CPP measures a learning process that is fun-distinct from drug SA. However, CPP paradigm hase particularly helpful in unmasking the motivationalof Cannabis derivates, although following repeatedul attempts [64], discrepant results [6571], or witharticular experimental conditions [72,73].ive body of evidence has revealed that the endo-d system, although not fundamental, constitutes anomponent in animal perception of the motivationalveral drugs of abuse and various other kinds of rein-fact, cannabinoids produce a significant effect onnaturadient oinducechowcannabCB1 r[64], ito enhforcersAsextendtion/retioninghow Cof nicorimonabut notest adexpresafter th3 or 1tionalcannabtive leprocestrainincannabCPP aTCH awhenand spseemsincent4. ChdensitWiticantlyseveradamidregionrepeatnicotinbrain a[8688encesConvesignifibrain [Accorin humneuronImpthe issccurring hallucinogen salvinorin A, the active ingre-lvia divinorum [80]. Moreover, they also affect CPPstandard and palatable food, i.e. sucrose and standardts. Indeed, consonant with a general role for endo-d transmission in appetitive motivational processes,tor antagonists block the acquisition of food-CPPative of the ability of the endocannabinoid systemperception of the rewarding value of different rein-SA paradigms, typical CPP protocols have beenand tailored into animal models of extinc-tement of a previously drug-induced place condi-this means, it has been possible to demonstratereceptor blockade impairs both the establishment-CPP (as pre-pairing injections of 3.0 mg kg1 i.p.t prevents acquisition of nicotine-CPP) and the short-g-term expression of nicotine-CPP (as a single pre-stration of the same dose of rimonabant abolished theof nicotine-CPP when the test session took place 24 ht conditioning session but not when it was conductedeks after conditioning) [81,82]. Therefore motiva-ts of nicotine appear to be controlled by endogenousds, although the long-term expression of such incen-ng seems to be independent of endocannabinoidFurthermore, when administered during extinctionw doses of THC and the non-psychoactive componentl (CBD), potentiate the extinction of both cocaine-mphetamine-CPP, at doses (0.251.0 mg kg1 i.p.mg kg1 i.p. CBD) not affecting learning or retrievalnistered singly [83]. Besides fear conditioning [84]l learning [85], the endocannabinoid system thuslay a critical role in the extinction of conditionedarning (Table 1).s in endocannabinoid contents, CB1 receptord function, and mRNA levelshe rat brain, endocannabinoid transmission is signif-red during chronic drug exposure, as described byies reporting marked changes in the content of anan-EA) and 2-arachidonyl-glycerol (2-AG) in cerebralated to reward and addiction. Specifically, not onlyministration of THC but also chronic alcohol andds to decreased AEA and 2-AG contents in the mid-an increased AEA formation in the limbic forebrainpporting the existence of region-dependent differ-e regulation of the two major endocannabinoids., chronic cocaine exhibited only a small, althoughdecrease in the 2-AG content in the limbic fore-while morphine induced no effect in AEA level [89].y, chronic ethanol was reported to increase AEAK-N-SH cells [90] and 2-AG in cerebellar granule1].ntly, a very recent paper by Caille et al. [92] addressedto whether changes in brain endocannabinoid con-422 L. Fattore et al. / Pharmacological Research 56 (2007) 418427Table 1Effect of drug primings on the reinstatement of extinguished drug self-administration (SA) behaviourPrevious SAWIN 55,212- temenWIN 55,212- temenWIN 55,212- ctHeroin temenHeroin temenHeroin ctHeroin nismHeroin temenAlcohol temenAlcohol temenAlcohol nismNicotine temenNicotine estigaCocaine ctCocaine temenCocaine nismMETH temenMETH nismAsterisks inditent also ocin vivo evidduring drustrates thatand 2-AG lSA does nobant (1.03cocaine SAing that CBwith cocainRegardlendocannaistrations adate only othe endocawhich the aand 2-AGalcohol afteAt celluing (down-activationadministrat[95,96]. Dethroughoutamong regireceptors wor CP 55,94CB1 receptin various bbant plus niincreased apocampal sexposure redesensitiza[87]. Accothe prefronomp104]ing)tingnsatalsevecongsityspeondidingte, md rat-2 (1fusionownPriming Effect2 WIN 55,212-2 Reinsta2 Heroin Reinsta2 Cocaine No effeWIN 55,212-2 ReinstaCP 55,940 ReinstaTHC No effeRimonabant/Heroin AntagoHU210 ReinstaTHC ReinstaDrug-associated cue ReinstaRimonabant/Alcohol AntagoDrug-associated cue ReinstaRimonabant/nicotine Not invTHC No effeHU210 ReinstaRimonabant/cocaine AntagoDrug-associated cue ReinstaRimonabant/METH Antagocate an effect reversible by pre-treatment with CB1 receptor antagonists.cur during voluntary drug intake by providing the firstence of variations in limbic endocannabinoid levelsg operant responding. This paper skillfully demon-ethanol SA and heroin SA differentially alter AEAevels in the rat nucleus accumbens, whereas cocainet. Accordingly, intra-accumbens injection of rimona-.0 mg kg1) reduced both ethanol and heroin, but not[92,93], in keeping with our previous studies show-1 receptor antagonism or deletion does not interferee SA [47,94].ess of the evidence of significant changes in brainbinoid signalling as a consequence of drug admin-nd more importantly of voluntary drug intake, tone study has been published on possible variations innnabinoid content during relapse to drug seeking, inuthors describe a significant reduction of both AEAcontents in the brains of rats allowed to relapse towhen clines [preferrsuggescompeof animHowrats intor denon theCPP ctor binopposiHoode55,212per inwell-kr abstinence [36].lar level, attenuation of both CB1 receptor bind-regulation) and CB1 agonist-stimulated G-protein(desensitization) occur after long-term cannabinoidion and are believed to contribute to tolerancecreased CB1 receptor level and efficiency take placethe brain, although the magnitude of changes variesons [9799]. For example, a down-regulation of CB1as observed following chronic treatment with THC0 [100102] but not cocaine [103]. Moreover, whileor-mediated G-protein signalling remained unalteredrain areas of rats given either rimonabant or rimona-cotine for 3-weeks CPP [82], CB1 receptor binding isnd decreased by chronic morphine in limbic and hip-tructures, respectively [103]. Finally, chronic alcoholsulted in a decreased number of CB1 receptors and ation of the cannabinoid-activated signal transductionrdingly, CB1 receptor binding was downregulated intal cortex of alcohol-preferring Alko Alcohol (AA)behaviouraAgain,alterationseither passiinvestigaterelapse toaddition toreported Cfied duringlimited to tChangelowing chrincrease Cthe cerebellevels in thdirection oOn the othmorphine dcaudate-puReferencest* Spano et al. [24]t* Spano et al. [24]Spano et al. [24]t* Fattore et al. [27]t* Fattore et al. [27]Fattore et al. [27]Fattore et al. [28]t* De Vries et al. [26]t McGregor et al. [37]t* Economidou et al. [35]Serra et al. [40]t* Cohen et al. [48]; De Vries et al. [49]ted Schenk and Partridge [50]t* De Vries et al. [41]De Vries et al. [41]; Filip et al. [52]t* Anggadiredja et al. [56]Anggadiredja et al. [56]ared to non-preferring Alko Non-Alcohol (ANA) ratand in the brain membranes of C57BL/6 (alcohol-with respect to DBA/2 (alcohol-avoiding) mice [91],an overactive endocannabinoid transmission and aory downregulation of CB1 signalling in the brainsgenetically selected for their preference for alcohol.r, when CB1 receptor binding is measured in operantruous results have been observed, with CB1 recep-and functionality varying differentially dependingcific drug used and the length of SA training ortioning. We recently demonstrated that CB1 recep-and functionality are altered in a differential, seldomanner in several reward-related brain areas of Listers trained to intravenously self-administer either WIN2.5g kg1 per infusion) or heroin (0.03 mg kg1n), providing a possible biochemical basis for theinteractions between opioid and CB1 receptors atl level [105].despite the body of evidence pointing to importantin CB1 receptor number and efficiency followingve or active drug exposure, only one study to date hasd possible variations in CB1 receptor binding duringdrug seeking after abstinence [36]. In this paper, inchanges in endocannabinoid content, authors alsoB1 receptor binding as being only minimally modi-relapse to alcohol, with a significant increase beinghe superficial layer of the cerebral cortex.s in CB1 receptor mRNA occur in the rat brain fol-onic exposure to THC, which has been shown toB1 mRNA levels above vehicle control animals inlum and hippocampus, and to severely reduce thesee striatum and caudate-putamen, the magnitude andf changes varying with treatment duration [106,107].er hand, both acute and chronic administration ofecreases the expression of the CB1 mRNA in thetamen, cerebellum and the shell portion of the nucleusL. Fattore et al. / Pharmacological Research 56 (2007) 418427 423Table 2Changes in endocannabinoid contents, CB1 receptor density and efficiencyduring relapse to alcoholBrain ChangeAEA content2-AG contentCB1 bindingCB1 mRNANo other studrelapse to othaccumbensserotonin rgene expregesting thain part, in tatric disordreduced CBthe ventrompocampusCB1 recepareas of dralcohol-prenon-selectemRNA levalcohol abuopposite fiin dorsal sdecreased bOnce agcontent andbeen conduing re-expobrains of anincreased msuperficialdial hypoththat mRNAdirection a5. DiscussAlthougin delineatand signallseeking be[111], internately stillpatients suregulatingnoid signacycle, from[114] to reData collecthe notioning episodthe importapy for drug and context-induced promotion of relapse to drugseeking.exase en. Cn fams, intarylogicrs inala [tiveli.e. congpse tinoipamidocad reorticen pthe ms bydocaThisce thl [12s innd driminoiothewnss codingd se30] sediatheotroplso be andpotatingtionnaptigraddocas Relapse to Alcohol Reference Gonzalez et al. [36] Gonzalez et al. [36] Gonzalez et al. [36] Gonzalez et al. [36]ies exist to date on possible variations of such parameters duringer drugs of abuse.[76,103,108], while repeated treatment with theeuptake inhibitor fluoxetine decreases CB1 receptorssion by approximately 4550% from vehicle, sug-t these neuroplastic changes may be involved, at leasthe clinical efficacy of cannabinoids in neuropsychi-ers [109]. Accordingly, chronic ethanol consumption1 receptor gene expression in the caudate-putamen,edial nucleus of the hypothalamus and in the hip-[110]. Conversely, an increased expression of thetor has been described in reward-relevant brainug-nave genetically selected Marchigian-Sardinianferring (msP) rats in comparison with drug-naved Wistar rats [42], pointing to a link between CB1els and distribution with genetic predisposition tose. However, this proposal has been hampered byndings, showing marked reductions of CB1 mRNAtriatum of AA rats, which was not accompanied byinding [104].ain, as previously described for endocannabinoidCB1 receptor binding, only one research study hascted so far to evaluate CB1 mRNA expression dur-sure to the drug after a period of abstinence. In theimals relapsing to alcohol, the latter study detected anRNA expression in the medial caudate-putamen, theand deep layers of the cerebral cortex, the ventrome-alamic nucleus and the hippocampus [36], indicatinglevels during relapse did not change in the sames during voluntary alcohol intake (Table 2).ionh in recent years enormous progress has been madeing biological features, neurocircuitry componentsing mechanisms mediating craving, conditioned drughaviour and long-lasting susceptibility to relapseventions directed at relapse prevention are unfortu-problematic and only effective in highly-motivatedTheate thequestiodomaiproteinubiquiphysionumbeamygdrespections (Amof relacannabthe dothe eninducemesochas beulaterewardby en[122].out mialcohotuationfood aated bycannabbe hyptem dotowardthe finto foonist [1(D3)-mOnmetabhave acocaining tomodulActivapre-sya retrothat enpported by stable social and affective conditions. Bythe brain reward circuits [112,113], endocannabi-lling is involved in almost all stages of addictionmaintenance of stably acquired addictive behaviourlapse to drug seeking following abstinence [59].ted to date from behavioural studies strongly supportthat the endocannabinoid system mediates relaps-es following cessation of drug intake, highlightingance of considering a CB1 antagonist-based ther-depolarisedsuppress ththat CB1 aby inhibitinnoids alsoGABAergirespective inot yet beethe oppositct brain location at which CB1 receptors medi-ffects on drug taking and seeking remains an openB1 receptors belong to the seven transmembraneily of G-protein-coupled receptors, are linked to Gi/ohibit adenylate cyclase [115,116], and are almostwithin the brain where they regulate a variety ofal functions [9]. For example, they are found in highthe ventral tegmental area and in the basolateral117,118], part of the corticolimbic circuit mediatingy drug-primed reinstatement and drug-cue associa-onditioning) [119,120].the neurotransmission pathways in which modulationo drug seeking is likely to be hampered by the endo-d system, particular emphasis has been focused onnergic system, as pharmacological manipulations ofnnabinoid system are believed to attenuate cocaine-instatement via inhibition of drug priming-inducedolimbic dopamine release [8,121]. Accordingly, itroposed that blockade of CB1 receptors might mod-otivational effects of drugs of abuse or naturalblocking the disinhibitory effects indirectly exertednnabinoids on mesolimbic dopaminergic neuronscould explain, for example, why in CB1 knock-e dopamine-releasing effects of morphine [123] and4] are significantly reduced or why dopamine fluc-the nucleus accumbens, known to accompany sex,rug seeking behaviour [125127], can all be attenu-onabant [128]. However, based on the evidence for addopamine interaction in the striatum [129], it couldsised that activation of the endocannabinoid sys-tream of the dopamine synapse may also contributecaine and heroin seeking [2628,51]. Nonetheless,that rimonabant blocks the potentiation of relapseeking induced by the dopamine D3 receptor ago-uggested an impact of CB1 blockade on dopamineted reward-related processes.other hand, N-methyl-d-aspartate (NMDA) andic glutamate (Glu) receptor (mGluR5) antagonistseen shown to prevent cue-induced reinstatement ofnicotine seeking, respectively [131,132], thus point-ential glutamateendocannabinoids interactions indiscrete cue-induced reinstatement of drug seeking.of post-synaptic Glu receptors is known to suppressc functions through the endocannabinoid system ine manner [133,134], lending support to the notionnnabinoids may act as retrograde messengers frompost-synaptic neurons to pre-synaptic terminals toe release of glutamate. In this view, one could arguentagonists may attenuate drug seeking reinstatementg glutamate release [135], even though endocannabi-act in a retrograde manner on axon terminals ofc interneurons to reduce GABA release [136]. Thentensities of these opposing Glu-GABA effects haven assessed, however some authors have proposed thate actions exerted by dopaminergic drugs (i.e. nico-424 L. Fattore et al. / Pharmacological Research 56 (2007) 418427tine) and endocannabinoids on glutamatergic and GABAergiccontrol over dopamine neurons in limbic area may representpossible mdrug-inducFinally,cade, knowcannabinoitem in relsupport ofstimulate avation of pprostaglandacid cascadof THC aninhibitor diReference[1] Hodginprecipi2004;7[2] Ledgerlogical[3] Mitcheeating29.[4] Pedersoeating[5] OBrieble new14233[6] Iwamomethod1988;8[7] Katz JLand rel[8] Shahamof drugmacolo[9] Ameri1999;5[10] Chhatwnoid nNeurop[11] Lin HCreceptoMem 2[12] KathurModulaMed 20[13] GobbiM, et aergic trSci 200[14] PiomelNeuros[15] Gardneof drug[16] Martelladminidrug-na[17] Fattoreadminiin rats.[18] Fattore L, Cossu G, Fratta W. Functional interaction between cannabi-noids and opioids in animal models of drug addiction. 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