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Relapse to Heroin-Seeking in Rats Under Opioid Maintenance: the Effects of Stress, Heroin Priming, and Withdrawal

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Relapse to Heroin-Seeking in Rats Under Opioid Maintenance: the Effects of Stress, Heroin Priming, and Withdrawal The Journal of Neuroscience, March 1, 1996, 76(5):1957-1963 Relapse to Heroin-Seeking in Rats under Opioid Maintenance: The Effects of Stress, Heroin Priming, and Withdrawal Yavin Shaham, Heshmat Rajabi, and Jane Stewart Center for Studies in Behavioral Neurobiology, Department of Psychology, Concordia University, Montreal, Quebec, Canada H3G lM8 It is widely believed that opioid withdrawal symptoms contrib- mals reinitiated heroin-seeking and, subsequently, both heroin ute to relapse to opioid use, but relapse is highly probable in and footshock reinstated heroin-seeking. In summary, brief experienced users even after prolonged abstinence and during exposure to stress reinstated heroin-seeking in both heroin- opioid maintenance therapy. We have found using an animal maintained and withdrawn animals. The heroin prime reliably model of relapse, the reinstatement procedure, that the two reinstated drug-seeking only in the absence of the minipump; events that reliably reinstate heroin-seeking behavior are reex- opioid “withdrawal,” as such, did not reinstate drug-seeking posure to heroin, and brief exposure to footshock stress. Con- behavior. Naloxone given to heroin-maintained animals in- trary to expectation, opioid antagonist-induced withdrawal duced withdrawal symptoms, caused a mild depression in the does not reinstate heroin-seeking. We now report on reinstate- levels of dopamine and its metabolites in the nucleus accum- ment of heroin-seeking in rats trained to self-administer heroin bens septi (NAS), but did not reinstate drug-seeking. Reinstate- and subsequently exposed to a maintenance dose of heroin via ment of heroin-seeking during spontaneous withdrawal was not minipump and allowed to self-administer saline. With the accompanied by reductions in basal dopamine and its metab- minipump in, naloxone-induced withdrawal did not reinstate olites in NAS. drug-seeking, a priming injection of heroin was only mildly effective, and footshock was highly effective. Twenty-four hours Key words: opioid self-administration; relapse; priming; after removal of the minipump (spontaneous withdrawal), ani- stress; withdrawal; nucleus accumbens; dopamine Theories of opioid self-administration posit a major role for mals is similar to those given lower dosesof morphine or heroin withdrawal symptomsin the maintenanceand relapse to drug- (for discussionof this issue,see Stewart and Eikelboom, 1987). taking after periodsof abstinence(Himmelsbach, 1943; Nichols et Furthermore, attempts to demonstratethat previous pairingsbe- al., 1956;Solomon and Corbit, 1974).Users have the opportunity tween exposureto the opioid drug and alleviation of withdrawal to learn that opioid drugs can alleviate the symptomsof with- would actually increasedrug-taking in a relapsephase have not drawal, and it makes sensethat when such symptoms occur been successful(Wikler and Pescor, 1967; Miller et al., 1979). experiencedusers might seekout and take thesedrugs. It hasbeen Studies by Wikler and others (Thompson and Ostlund, 1965; suggested,furthermore, that because opioid-like withdrawal Wikler and Pescor,1967; Wikler et al., 1971;Sobrero and Bouton, symptomscan be evoked by drug-related stimuli through associa- 1989) have also failed to demonstratethat a conditioned state of tive conditioning, thesestimuli, by evoking withdrawal symptoms, withdrawal evoked by presentation of stimuli previously paired can induce relapseeven after long periods of abstinence(Wikler, with opioid withdrawal can induce relapse to drug use (see also 1973;Siegel, 1977;O’Brien et al., 1986). Stewart et al., 1984). Furthermore, in humanswithdrawal symp- Despite many years of research,however, a major role for the toms evoked by exposureto drug-related cuesare only modestly state of withdrawal in compulsiveopioid use and relapsehas not related to self-reportsof craving (Childresset al., 1986;O’Brien et been established.It has been difficult to demonstratein animals al., 1992). any motivational role for withdrawal statesin opioid-taking (Stew- Despite the lack of evidencefor a positive relationshipbetween art et al., 1984),and attemptsto reinstate heroin-seekingbehavior the state of withdrawal and relapse, the opioid-withdrawal syn- by precipitating withdrawal directly have met with failure (Sha- drome is receiving considerableattention as an important con- ham and Stewart, 1995b).Animals self-administeringmorphine or tributor to drug-seekingbehavior in the drug-free state. The heroin have been shown to take more of the drug when given revival of this view (Koob et al., 1992) is attributable largely to injections of an opioid antagonist, but the behavior of such ani- recent observationsmade using microdialysisthat opioid antago- nists given to morphine-dependentrats precipitate withdrawal Received Oct. 2, 1995; revised Nov. 27, 1995; accepted Dec. 11, 1995. symptomsand decreaseextracellular dopamine(DA) overflow in This research was supported by grants to J.S. from the Medical Research Council nucleusaccumbens septi (NAS) (Pothos et al., 1991; Rossettiet of Canada and from the Foods pour la Formation de Chercheurs et I’Aide ?I la al., 1992), whereas injections of opioid agonists increase DA Recherche (QuCbec). Y.S. holds a Postdoctoral Fellowship from the Medical Re- search Council of Canada. We thank Jennifer Puddicombe and Demetra Rodaros for overflow in this brain region (Di Chiara and Imperato, 1988).The their expert technical assistance. reasonthis is consideredsignificant is that increasedDA activity Correspondence should be addressed to Jane Stewart, Center for Studies in in this region of the brain has been shownto be correlated with Behavioral Neurobiology, Department of Psychology, Concordia University, 1455 de Maisonneuve Boulevard, Montreal, Quebec, Canada H3G lM8. the positive-reinforcingeffects of opioid drugs(Shippenberg et al., Copyright 0 1996 Society for Neuroscience 0270-6474/96/161957-07$05.00/O 1992;Devine et al., 1993; Devine and Wise, 1994).Furthermore, 1958 J. Neurosci., March 1, 1996, 76(5):1957-1963 Shaham et al. Relapse to Heroin-Seeking under Opioid Maintenance Experimental Design Minipump IN I 8 If B Group jj j four3-h one 7-h 3 one7-h I-B reinstatement I sessions/day r session/day r session/day I one 3-h session/test Minipiump IN ! I I I I t 1 Minipump OUT , Figure 1. Diagram showing the sequence of treatments bB reinstatement of the Minipump IN and the Minipump OUT groups in the I I I , one 3-h session/test Minipump OUT i I I study of reinstatement. I I it has been shown that blockade of D, DA receptors in the NAS above the floor, but only one lever (an “active,” retractable lever; Med can elicit somatic withdrawal symptoms in morphine-dependent Associates, Lafayette, IN) activated the infusion pump (Raze1 Scientific rats, whereas injections of D, DA receptor agonists into the NAS Instruments, Stamford, CT). Presses on the other lever (“dummy,” sta- tionary lever) were recorded, but did not activate the infusion pump. A attenuate naloxone-precipitated withdrawal symptoms in these given drug dose was infused at a volume of 0.13 ml during a 20 set period. rats (Harris and Aston-Jones, 1994). Such studies suggest that the During the infusion, a light located above the active lever was lit for 20 mesolimbic DA system may be involved in both opioid reinforce- sec. Bar presses during those 20 set were counted, but did not lead to ment and opioid withdrawal, but they do not address directly the further infusions. The grid floors of the chambers were connected to question of the relationships among symptoms of opioid with- electric shock generators. Drugs. Diacetylmorphine HCI (heroin) was obtained from Health and drawal, decreased levels of extracellular DA in the NAS, and Welfare office of Canada. Naloxone HCI was obtained from DuPont relapse to drug use. NEN (Wilmington, DE). Drugs were dissolved in physiological saline. In previous studies, we have found two events to be highly Procedure. Figure 1 outlines the scqucnce of treatments given to the effective in reinstating heroin-seeking, a priming injection of her- two groups studied. Animals were trained to self-administer heroin (100 oin itself, and brief exposure to footshock stress; however, Kg/kg per infusion) over 4-5 d, during which each lever press was reinforced. Each day was divided into four 3 hr sessions (2 during the naltrexone-precipitated withdrawal was ineffective. The fact that dark and 2 during the light) separated by 3 hr. The first session of each both the priming injection of heroin and footshock led to in- day started at the beginning of the dark period, 10 A.M. Throughout the creased levels of DA in NAS, whereas injection of naltrexone 40 experiment, each session began by the introduction of the retractable min after exposure to morphine (precipitated withdrawal) re- lever into the cage and the illumination of the white light above the lever versed morphine-induced elevations in DA levels, brings into for 30 sec. A red house-light was turned on for the entire session. After question a direct link between depressed DA levels and relapse training rats were allowed to self-administer heroin for 6-7 d, one 7 hr session/d (10 A.M. to 5 P.M.). These 7 hr daily sessions were instituted to (Shaham and Stewart, 1995a,b). allow the animals to associate the administration of heroin with the In the present study, we approached the question of the con- alleviation opioid withdrawal. Opioid withdrawal symptoms are maxima1 ditions for reinstatement of heroin-seeking and, in particular, the 12-24 hr after
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