An endocannabinoid mechanism in relapse to drug seeking: A review of animal studies and clinical perspectives

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  • Review

    An endocannabinoidA review of animal s

    Liana Fattorea,c,, M. SabrinaPaola Faddab,c, Walter FrattaaInstitute of Neuroscience, National ResearchbDepartment of Neuroscience, Cittadella Unive

    Depend

    B R A I N R E S E A R C H R E V I E W S 5 3 ( 2 0 0 7 ) 1 1 6

    ava i l ab l e a t www.sc i enced i rec t . com

    www.e l sev i e r. com/ loca te /b ra in res revsystem and the neurobiological mechanisms leading to relapse. For each class of abuseddrugs, the conspicuous progress made in delineating the role of the endocannabinoidsystem in relapse to drug seeking has been examined by placing particular emphasis on thefindings obtained from behavioral studies. After summarizing findings and implicationsemerging from the reviewed studies, we conclude by briefly discussing what information isstill missing and how missing information might be obtained.

    2006 Elsevier B.V. All rights reserved.cue-induced reinstatement of drug seeking behavior. Indeed, while CB-sub1 receptorstimulation may elicit relapse not only to cannabinoid seeking but also to cocaine, heroin,alcohol and methamphetamine, this effect is significantly attenuated, when not fullyprevented, by pretreatment with the CB-sub1 receptor antagonist rimonabant. However,corroborating data on the involvement of the cannabinoid system in stress-inducedreinstatement are still rather scarce. The present review attempts to collect data obtainedfrom different laboratories using diverse experimental approaches, to provide acomprehensive picture of the recent evidence of a relationship between the cannabinoid

    ExtinctionDrug addictionDrug seekingReinstatement Corresponding author. Institute of NeuroUniversitaria di Monserrato, University of Ca

    E-mail address: lfattore@ca.cnr.it (L. Fatto

    0165-0173/$ see front matter 2006 Elsevidoi:10.1016/j.brainresrev.2006.05.003regulation of relapsing phenomena. Both stimulation and blockade of the centralcannabinoid CB-sub1 receptor have proved to play an important role in drug- as well as inKeywords:EndocannabinoidRelapsemechanism in relapse to drug seeking:tudies and clinical perspectives

    Spanob,c, Serena Deianab, Valeria Melisb, Gregorio Cossub,c,a,b,c

    Council CNR, Section of Cagliari, Italyrsitaria di Monserrato, University of Cagliari, Italyence, Cittadella Universitaria di Monserrato, University of Cagliari, Italy

    A B S T R A C T

    Detoxification from drug abuse is strongly threatened by the occurrence of renewedepisodes of drug intake. In human addicts, relapse to drug seekingmay take place even aftera considerably long period from the last drug consumption. Over the last decade, theendocannabinoid system has received remarkable attention due to its unique features,including its rewarding properties closely resembling those of the most commonly abusedsubstances and its multiple therapeutic implications. Although limited at present, evidenceis now emerging on a possible participation of the endogenous cannabinoid system in thecCentre of Excellence Neurobiology of

    A R T I C L E I N F O

    Article history:Accepted 8 May 2006Available online 12 July 2006science, National Research Council CNR, c/o Department of Neuroscience, Cittadellagliari, 09042 Monserrato (Cagliari), Italy. Fax: +39 0 70 6754312.re).

    er B.V. All rights reserved.

  • receptor

    . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2imulation on drug seeking reinstatement . . . . . . . . . . . . . . . . . . . . . . . . . . . 3tement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4ment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7atement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7ockage on drug seeking reinstatement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8tement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8ment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8atement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

    tion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

    reatment of drug abuse isseeking after abstinence.

    ise mechanisms triggeringpharmacological/psycho-

    abuse (i.e., heroin) of a few proven effective approaches foruse in crisis intervention, detoxification, stabilization andharm reduction for addicted patients. That is, naloxone maybe effective in treating respiratory depression and coma inpatients with opioid overdose, detoxification can beachieved with opioid agonists (i.e., methadone, buprenor-

    V Ipyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)-methanonemesylate

    Contents

    1. Introduction . . . . . . . . .2. Effect of CB-sub1 receptor st

    2.1. Drug-induced reinsta2.2. Cue-induced reinstate2.3. Stress-induced reinst

    3. Effect of CB-sub1 receptor bl3.1. Drug-induced reinsta3.2. Cue-induced reinstate3.3. Stress-induced reinst

    4. Clinical findings . . . . . . .5. Possible neural targets of ac6. Concluding remarks . . . . .Acknowledgment . . . . . . . . .References. . . . . . . . . . . . .

    1. Introduction

    One of the major problems in the tthe reinitiating of drug craving andA better understanding of the precrelapse strikes at the very core of

    logical treatment of drug addiction and dexperience has reported the availability fmethyl-3-[(morpholinyl)methyl]-VTA, ventral tegmental areaWIN 55,212-2, R(+)-[2,3-dihydro-5-CP 55,940, ()-cis-3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclo-hexanolDA, dopamine9-THC, delta9-tetrahydrocannabinolGABA, gamma-aminobutyric acidHU210, 3-(1,1-dimethylheptyl)-11-hydroxy-8-tetrahydro-cannabinolMETH, methamphetamineNAcc, nucleus accumbensNMDA, N-methyl-D-aspartateSR 141716A, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox-amide hydro-chlorideAbbreviations:AMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acidCB-sub1, type 1 cannabinoidreceptorCB-sub2, type 2 cannabinoid

    2 B R A I N R E S E A R C H R Eependence. Clinicalor specific drugs ofE W S 5 3 ( 2 0 0 7 ) 1 1 6phine) or 2-adrenergic agonists (i.e., clonidine, lofexidine),and prevention of relapse may be supported by naltrexone.

  • nicotine (Casta et al., 2005; Cohen et al., 2002, 2004),

    V IThe latter strategies however proved somewhat problematicdue to low compliance and effectiveness as well as themanifestation of side effects, such as depression or anhe-donia (Van den Brink and van Ree, 2003). Besides heroin,individuation of successful strategies aimed at preventingrelapse to other drugs of abuse in abstinent individuals isstill problematic, in view also of the fact that the formerhave proved beneficial only in strongly motivated subjects.Thus, recurrence of relapsing episodes in long-term absti-nent patients represents one of the most significant andpuzzling problems during disintoxication. In many ways, theproblem is central to the whole enterprise of drug abuse anddependence research, in its attempt to provide a feasiblescientific account of the brain circuits underlying relapse todrug seeking and drug taking.

    The most commonly used approach to modeling humanrelapse to craving and drug seeking following abstinence inlaboratory animals is the extinction/reinstatement paradigm,in which an animal is initially trained to operate (by lever-pressing or nose-poking) in order to self-administer the drug.Once the animal has learned this specific task, the drug iswithheld even though the animal continues to operate toobtain the drug. After a while, the rat stops pressing the leveror making nose-poking responses, indicating the extinguish-ing of self-administration behavior. Following extinction,various stimuli may be acutely presented to assess whetherthey are able to reinstate drug seeking behavior, i.e., if theycause renewed operant responding even if the animal doesnot receive the drug. At least three types of stimuli canreinstate responding: (i) a single injection of the samepreviously experienced drug (i.e., drug priming), (ii) a condi-tioned stimulus that was contingently paired during the initialtraining sessions with the delivery of the drug and (iii) stressfactors.

    Among the neuronal systems involved in the resumptionof drug seeking behavior following extinction particularattention has recently been paid to endogenous cannabinoidtransmission. Our understanding of the endocannabinoidsystem has advanced enormously since the identification ofthe CB-sub1 and CB-sub2 cannabinoid receptors (Howlett etal., 1990; Matsuda et al., 1990; Munro et al., 1993; Grard etal., 1991; Mailleux and Vanderhaeghen, 1992; Glass et al.,1997), the discovery of the endogenous ligands anandamideand 2-arachidonoylglycerol (Devane et al., 1992; Mechoulamet al., 1995; Sugiura et al., 1995) and the detection of theirbiosynthesis and degradation pathways (Di Marzo et al.,1994, Stella et al., 1997). Endocannabinoids have beenproposed to act as retrograde signaling messengers inGABAergic and glutamatergic synapses (Wilson and Nicoll,2001; Kreitzer and Regehr, 2002; Piomelli, 2003) and modulatepost-synaptic transmission by interacting with many otherneurotransmitters (Wilson and Nicoll, 2002). Although afterrepeat