Drug Wanting: Behavioral Sensitization and Relapse to Drug-Seeking Behavior

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<ul><li><p>ASSOCIATE EDITOR: DAVID R. SIBLEY</p><p>Drug Wanting: Behavioral Sensitization and Relapse toDrug-Seeking Behavior</p><p>Jeffery D. Steketee and Peter W. Kalivas</p><p>Department of Pharmacology, University of Tennessee Health Science Center, Memphis, Tennessee (J.D.S.); and Department ofNeurosciences, Medical University of South Carolina, Charleston, South Carolina (P.W.K.)</p><p>Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348I. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349</p><p>II. Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349A. Sensitization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349B. Relapse/reinstatement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350C. Behavioral relationships between sensitization and relapse. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351</p><p>III. Neurocircuitry. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351A. Neurons versus circuits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351B. Sensitization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351C. Relapse/reinstatement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353D. Neural circuitry relationships between sensitization and relapse . . . . . . . . . . . . . . . . . . . . . . . . . . 353</p><p>IV. Neurochemistry/neuropharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354A. Sensitization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354</p><p>1. Dopamine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3542. Dopamine receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3543. Glutamate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3554. Glutamate receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3565. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357</p><p>B. Reinstatement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3581. Dopamine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3582. Glutamate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3583. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359</p><p>C. Neurochemical/neuropharmacological relationships between sensitization and relapse. . . . . . . 360V. The role of sensitization in relapse to drug-seeking behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360</p><p>VI. Therapeutic implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361</p><p>AbstractRepeated exposure to drugs of abuseenhances the motor-stimulant response to thesedrugs, a phenomenon termed behavioral sensitiza-tion. Animals that are extinguished from self-admin-istration training readily relapse to drug, condi-tioned cue, or stress priming. The involvement ofsensitization in reinstated drug-seeking behavior</p><p>remains controversial. This review describes sensi-tization and reinstated drug seeking as behavioralevents, and the neural circuitry, neurochemistry, andneuropharmacology underlying both behavioral modelswill be described, compared, and contrasted. It seemsthat although sensitization and reinstatement involveoverlapping circuitry and neurotransmitter and recep-tor systems, the role of sensitization in reinstatementremains ill-defined. Nevertheless, it is argued that sen-sitization remains a useful model for determining theneural basis of addiction, and an example is provided inwhich data from sensitization studies led to potentialpharmacotherapies that have been tested in animalmodels of relapse and in human addicts.</p><p>Address correspondence to: Jeff Steketee, Department of Pharma-cology, University of Tennessee Health Science Center, 874 UnionAvenue, Memphis, TN 38163. E-mail: jsteketee@uthsc.edu</p><p>This article is available online at http://pharmrev.aspetjournals.org.doi:10.1124/pr.109.001933.</p><p>0031-6997/11/6302-348365$25.00PHARMACOLOGICAL REVIEWS Vol. 63, No. 2Copyright 2011 by The American Society for Pharmacology and Experimental Therapeutics 1933/3681868Pharmacol Rev 63:348365, 2011 Printed in U.S.A.</p><p>348</p><p> at Um</p><p>ea University Library on A</p><p>ugust 26, 2014pharm</p><p>rev.aspetjournals.orgD</p><p>ownloaded from</p><p>http://pharmrev.aspetjournals.org/</p></li><li><p>I. Introduction</p><p>Substance abuse is a chronic and enduring phenome-non. Extensive investigations regarding the underlyingneural mechanisms of addiction have been ongoing forthe past 3 decades. Despite these efforts, few effectivetreatment options are available to treat drug depen-dence. Animal models of substance abuse include bothnoncontingent (experimenter-administered) and contin-gent (self-administered) drug administration. Up untilthe late 1990s, studies on drug-induced neuroplasticityfocused primarily on examining the effects of repeatednoncontingent drug treatments (i.e., sensitization) ondopamine and glutamate systems (Kalivas and Stewart,1991; Vanderschuren and Kalivas, 2000). Although non-contingent drug administration has provided a wealth ofdata on how repeated drug exposure alters neuronalfunction, it is not always accepted that these data pre-dict the neuroplasticity associated with contingent drugadministration. Therefore, recent studies have focusedon contingent drug self-administration and, in particu-lar, reinstatement of drug-seeking behavior. The choiceof this model is based on the idea that the treatments ofaddiction will intervene to prevent relapse, which rein-statement behavior purports to model (Epstein et al.,2006). Both the sensitization and reinstatement modelsassess the impact of repeated drug exposure on neuralfunction, the primary difference being how the drug isadministered. Thus, the present review will compareand contrast the neural consequences of drug treatmentin contingent and noncontingent behavioral models ofaddiction used to study the neural consequences of drugadministration. We then explore questions regardingthe interchangeability and validity of each model with agoal to determine the extent of predictive validity thatbehavioral sensitization resulting from repeated noncon-tingent drug administration provides for the neuroplastic-ity underlying the reinstatement of extinguished contin-gent drug self-administration. Furthermore, whetherbehavioral sensitization is a component of reinstatement ofdrug seeking behavior will also be considered.</p><p>II. Definitions</p><p>A. Sensitization</p><p>The enhanced response to a stimulus, after repeatedexposure to that stimulus, is termed sensitization (Rob-inson and Becker, 1986; Kalivas and Stewart, 1991).Regarding drugs of abuse, behavioral sensitization isdefined by the augmented motor-stimulant responsethat occurs with repeated, intermittent exposure to aspecific drug. Behavioral sensitization is a long-lastingphenomenon; the enhanced behavioral response hasbeen reported to persist for at least a year (Paulson etal., 1991). A number of factors, including number oftreatments, interval between treatments, dose, sex, age,and genetics, can affect the strength of behavioral sen-</p><p>sitization (Post and Contel, 1983). Behavioral sensitiza-tion has been reported to occur in response to cocaine,amphetamine, morphine, ethanol, nicotine, and 9-tet-rahydrocannabinol (Joyce and Iversen, 1979; Robinsonand Becker, 1986; Benwell and Balfour, 1992; Cunning-ham and Noble, 1992; Post et al., 1992; Cadoni et al.,2001). Furthermore, cross-sensitization between drugshas been shown. For example, animals repeatedly ex-posed to 9-tetrahydrocannabinol exhibited a sensitizedbehavioral response to morphine (Cadoni et al., 2001),whereas animals repeatedly exposed to ethanol weresensitized to cocaine and vice versa (Itzhak and Martin,1999), and animals repeatedly exposed to amphetaminewere sensitized to morphine (Lett, 1989; Vezina et al.,1989; Vezina and Stewart, 1990). In addition, animalswith a history of repeated exposure to toluene, via inha-lation, exhibited a behaviorally sensitized response tococaine (Beyer et al., 2001). This suggests that commonmechanisms underlie the development of behavioralsensitization, despite the fact that different classes ofdrug have distinct binding sites in the brain.</p><p>The development of behavioral sensitization can beseparated into two phases: initiation and expression.Initiation is the immediate neural events that inducebehavioral sensitization, and expression is the long-termconsequences of these initial events (Kalivas and Stew-art, 1991). Initiation is commonly linked to the ventraltegmental area (VTA1), and expression is associatedwith the nucleus accumbens. The environment can in-fluence both the initiation and expression of behavioralsensitization. Thus, animals repeatedly exposed todrugs such as cocaine, amphetamine, or morphine dur-ing the initiation phase expressed more robust sensiti-zation when re-exposed to drug in the same environment(paired) as previous drug exposure during the expres-sion phase, compared with animals tested in an environ-ment that differed (unpaired) from that used during theinitiation phase (Vezina et al., 1989; Anagnostaras andRobinson, 1996; Wang and Hsiao, 2003; Mattson et al.,2008; Vezina and Leyton, 2009). Behavioral sensitiza-tion in the paired environment is commonly referred toas context-dependent sensitization as opposed to con-</p><p>1Abbreviations: AMPA, -amino-3-hydroxyl-5-methyl-4-isoxazole-propionate; CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione; CPP, condi-tioned place preference; CRF, corticotropin-releasing factor; GluR,glutamate receptor; JNJ16259685, (3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone; LDT, laterodorsaltegmentum; LTP, long-term potentiation; LY341495, 2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine; LY379268,(1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid;mGluR, metabotropic glutamate receptor; mPFC, medial prefrontalcortex; NMDA, N-methyl-D-aspartate; PPT, pedunculopontine tegmen-tum; PVN, paraventricular nucleus; SCH23390, (R)-()-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; SKF81297, ()-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide; SKF38393, 2,3,4,5-tetrahydro-7,8-dihy-droxy-1-phenyl-1H-3-benzazepine; SKF82958, ()-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetra-hydro-1H-benzazepine; VTA,ventral tegmental area.</p><p>SENSITIZATION AND REINSTATEMENT 349</p></li><li><p>text-independent sensitization, which occurs in an un-paired paradigm. Context-dependent cross-sensitizationhas also been reported to occur (Vezina et al., 1989).</p><p>Behavioral sensitization is commonly assessed bymonitoring motor activity. When monitoring motor ac-tivity, repeated exposure to drugs leads to an augmentedmotor-stimulant response. Sensitization to amphet-amine-like psychostimulants can escalate to manifest asintensified stereotypic behavior that competes with lo-comotion. For example, when rats are sensitized tohigher doses of amphetamine (e.g., 2.0 mg/kg i.p.), theyshow an initial reduction in activity in response to am-phetamine challenge, followed by a delayed increase inlocomotor activity (Leith and Kuczenski, 1982). Behav-ioral sensitization can also be assessed via conditionedplace preference (CPP) or drug self-administration. Inthe CPP paradigm, sensitization is manifested as en-hanced time spent in the drug-paired chamber. Thuscocaine, amphetamine, and morphine-induced CPP wasenhanced in animals with a history of repeated exposureto these drugs (Lett, 1989; Shippenberg et al., 1996). Thepotential involvement of sensitization in drug self-ad-ministration is usually determined by the ability of re-peated noncontingent drug exposure to enhance the ac-quisition of drug self-administration, using low drugdoses, or by drug self-administration inducing locomotorsensitization in response to a noncontingent drug injec-tion (Vezina, 2004). It was initially demonstrated thatanimals with a history of experimenter-administeredamphetamine, which induced locomotor sensitization,subsequently showed an augmented acquisition ofamphetamine self-administration (Piazza et al., 1990).Furthermore, pre-exposure to amphetamine, 3,4-methyl-enedioxy methamphetamine, or nicotine enhanced vulner-ability to self-administration of cocaine (Horger et al.,1992; Fletcher et al., 2001). Subsequent studies demon-strated that animals with a history of intravenous cocaineor heroin self-administration demonstrate a sensitized mo-tor response to a systemic challenge injection of the self-administered drug (Hooks et al., 1994; Phillips and DiCiano, 1996; De Vries et al., 1998b; Zapata et al., 2003). Inaddition, it was shown that when motor activity was mon-itored during self-administration, sensitization to the stim-ulant properties of heroin developed (Marinelli et al.,1998). Animals that self-administered heroin also showedcross-sensitization to noncontingent amphetamine-in-duced locomotion (De Vries et al., 1998b). Finally, it hasbeen reported that repeated, noncontingent admin...</p></li></ul>

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