Interaction of noncontingent cocaine and contingent drug-paired stimuli on cocaine reinstatement
Introduction
Relapse to drug use following a period of abstinence is a major problem in drug abusers. Many detoxified drug abusers report that they relapsed due to craving induced by the environment that was previously associated with drug taking O'Brien et al., 1977, Sideroff and Jarvik, 1980, Wallace, 1989. Other abstinent drug abusers report that craving followed exposure to the previously abused drug McCaul et al., 1989, Chornock et al., 1992. Although both interoceptive and external environmental variables are believed to play significant roles in relapse, the interaction of the two is not well understood (Childress et al., 1993).
The drug reinstatement paradigm in animals is frequently used to explore the factors underlying relapse and has been theorized to model some aspects of human drug craving and relapse Koob, 2000, Littleton, 2000. In reinstatement studies, operant responding resulting in drug injections is extinguished after a period of drug availability. Following extinction, noncontingent presentation of the previously self-administered drug or a pharmacologically similar drug will result in renewed responding on the manipulandum that previously produced drug injections (Shaham et al., 2002). The magnitude of drug-induced reinstatement has been shown to be dose-dependent, with low doses producing less robust reinstatement than moderate or high doses (Schenk and Partridge, 1999). External stimuli, typically light and/or tones that have been repeatedly paired with drug delivery, will also reinstate operant responding when presented response contingently, and to a lesser degree when presented noncontingently during reinstatement testing Gerber and Stretch, 1975, Arroyo et al., 1998, Weiss et al., 2001. Exposure to a specific environment that has been intentionally paired with the opportunity to self-administer cocaine will also result in significant, albeit transient, reinstatement responding (Alleweireldt et al., 2001).
Few studies have explicitly examined the interaction between interoceptive drug effects and contingent drug-paired external stimuli on the magnitude of subsequent reinstatement. One experiment in squirrel monkeys found that drug-paired external stimuli combined with a noncontingent drug injection resulted in more pronounced reinstatement responding than either the external stimuli or drug alone (Spealman et al., 1999). A second study in cocaine-trained rats demonstrated that noncontingent presentation of drug-associated external stimuli in combination with an injection of d-amphetamine produced greater reinstatement and enhancement of dopamine efflux in the nucleus accumbens than d-amphetamine or noncontingent stimuli alone (Di Ciano et al., 2001).
The major goal of the present study was to determine the degree of interaction between noncontingent cocaine dose and response contingent drug-paired external stimuli on reinstatement. To examine this interaction, three different noncontingent cocaine doses were initially presented alone immediately prior to reinstatement testing. These same three doses of cocaine were subsequently presented in combination with response-contingent flashing lights+tone. Finally, only the response contingent flashing lights+tone were presented during reinstatement testing.
Section snippets
Subjects
Subjects were 32 adult, male, experimentally naı̈ve Sprague–Dawley (Charles River Laboratories, USA) rats. Animals were food-restricted to 15 g of rodent chow per day and had continuous access to water except during the experimental sessions. Rats weighed at least 275 g at the beginning of the study. The animals were individually housed in standard plastic rodent cages in a temperature-controlled (22° C) 12-h reversed light/dark cycle colony room. Studies were approved by the Institutional
Results
Rats readily acquired self-administration of 0.5 mg/kg/infusion cocaine. Averaged across rats, a mean of 15.9 (±1.1) cocaine self-administration sessions were required to reach FR5 and meet criteria for beginning extinction. A mean of 29.4 (±1.7) cocaine infusions were obtained on the last day of cocaine self-administration training. During extinction, an average of only 2.8 (±0.3) days were required to reach reinstatement testing criteria. Neither total infusions on the final day of
Discussion
The results in the present study show that under some conditions neither noncontingent cocaine nor contingent cocaine-paired external stimuli presentation may be effective in reinstating extinguished cocaine-reinforced behavior. However, their concurrent presentation may powerfully evoke such behavior beyond that expected by their individual contributions and do so repeatedly for several days. Although both noncontingent cocaine and contingent cocaine-paired external stimuli have been
Acknowledgements
This work was supported by NIDA contract N01DA-0-8801. The authors would like to thank Ms. Kelly Silver-Wade and Ms. Kelly Kinzer for their excellent technical assistance.
References (26)
- et al.
Passive exposure to a contextual discriminative stimulus reinstates cocaine-seeking behavior in rats
Pharmacol. Biochem. Behav.
(2001) - et al.
Changes in dopamine efflux associated with extinction, CS-induced and d-amphetamine-induced reinstatement of drug-seeking behavior by rats
Behav. Brain. Res.
(2001) - et al.
Alpha-2 adrenergic receptor agonists block stress-induced reinstatement of cocaine seeking
Neuropsychopharmacology
(2000) - et al.
Drug-induced reinstatement of extinguished self-administration behavior in monkeys
Pharmacol. Biochem. Behav.
(1975) - et al.
Pharmacological and environmental determinants of relapse to cocaine-seeking behavior
Pharmacol. Biochem. Behav.
(1999) Psychological and environmental determinants of relapse in crack cocaine smokers
J. Subst. Abuse Treat.
(1989)- et al.
Enduring resistance to extinction of cocaine-seeking behavior induced by drug-related cues
Neuropsychopharmacology
(2001) - et al.
Reinstatement of extinguished cocaine-taking behavior by cocaine and caffeine
Pharmacol. Biochem. Behav.
(1994) - et al.
Acquisition, maintenance and reinstatement of intravenous cocaine self-administration under a second-order schedule of reinforcement in rats: effects of conditioned cues and continuous access to cocaine
Psychopharmacology
(1998) - et al.
Cue reactivity and cue reactivity interventions in drug dependence
NIDA Res. Monogr.
(1993)
Experimental model of smoking re-exposure: effects on relapse
Psychopharmacology
Second-order schedules of drug reinforcement in rats and monkeys: measurement of reinforcing efficacy and drug-seeking behaviour
Psychopharmacology
Predictive validity of the extinction/reinstatement model of drug craving
Psychopharmacology
Cited by (9)
Efficacy of buspirone for attenuating cocaine and methamphetamine reinstatement in rats
2013, Drug and Alcohol DependenceCitation Excerpt :During drug priming reinstatement studies, separate groups of rats received either an injection of 17 mg/kg i.p. cocaine 10 min before the start of the reinstatement test session or 1 mg/kg i.p. methamphetamine 30 min prior to the start of the reinstatement test session. Cocaine and methamphetamine priming dose was chosen based on prior studies from the laboratory showing they produced robust and generally comparable reinstatement magnitudes (Shelton and Beardsley, 2008; Shelton et al., 2004). A total of 36 rats were used for each of the 4 individual studies, 12 in each buspirone dose or vehicle condition.
The selective dopamine uptake inhibitor, D-84, suppresses cocaine self-administration, but does not occasion cocaine-like levels of generalization
2010, European Journal of PharmacologyCitation Excerpt :A 5-w house light and Sonalert® tone generator were located on the rear wall of the chamber. After acclimation to the vivarium, indwelling venous catheters were implanted into the right external jugular vein using procedures and catheters similar to that described previously (Shelton and Beardsley, 2005; Shelton et al., 2004). Rats were allowed to recover from surgery for at least 5 days before self-administration training began.
Mouse model of relapse to the abuse of drugs: Procedural considerations and characterizations
2009, Behavioural Brain ResearchEffect of drug-paired exteroceptive stimulus presentations on methamphetamine reinstatement in rats
2008, Pharmacology Biochemistry and BehaviorReinstatement of nicotine-conditioned place preference by drug priming: Effects of calcium channel antagonists
2006, European Journal of Pharmacology