Dopamine D1- and D2-Like Receptor Mechanisms in Relapse to Cocaine-Seeking Behavior: Effects of Selective Antagonists and Agonists1
Abstract
Dopaminergic mechanisms are thought to be critical in mediating relapse to cocaine-seeking behavior. This study examined the different roles of D1- and D2-like receptor mechanisms in the relapse process. Squirrel monkeys were given extended histories of i.v. cocaine self-administration under conditions in which responding was maintained jointly by response-contingent cocaine injections and a cocaine-paired visual stimulus (second-order schedule). Responding was then extinguished by substituting saline for cocaine injections and omitting presentations of the cocaine-paired stimulus. Subsequently, noncontingent priming injections of cocaine combined with restoration of the cocaine-paired stimulus induced dose-dependent reinstatement of drug-seeking behavior, with response rates approaching those maintained by active cocaine self-administration. The priming effects of cocaine were attenuated by several D1- and D2-like receptor antagonists and low efficacy agonists but not by the D3-preferring antagonists UH 232 and AJ-76. The priming effects of cocaine were mimicked by the D2-like receptor agonists R(−)-propylnorapomorphine hydrochloride (NPA) and quinpirole, less consistently by 7-OH-DPAT, and not by the D1-like receptor agonists SKF-81297 and SKF-82958, the D3-preferring agonist PD-128,907, or any low efficacy agonist. Cotreatment with NPA, PD-128,907, and 7-OH-DPAT did not alter reinstatement of drug-seeking behavior induced by a maximally effective priming dose of cocaine, whereas cotreatment with D1-like receptor agonists attenuated the priming effects of cocaine. The results suggest that D1- and D2-like receptors play fundamentally different roles in the relapse process. Although stimulation of D2-like, but probably not D3-like, receptors appears necessary for induction of relapse, either stimulation or blockade of D1-like receptors appears to be inhibitory with respect to relapse.
Footnotes
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Send reprint requests to: Roger Spealman, Ph.D., Harvard Medical School, New England Regional Primate Research Center, One Pine Hill Dr., Box 9102, Southborough, MA 01772-9102. E-mail:roger_spealman{at}hms.harvard.edu
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↵1 This research was supported by National Institutes of Health Grants DA11054, DA00499, and RR00168 and by an unrestricted grant from the Schering-Plough Research Institute. Preliminary reports of these data were presented at the annual meetings of the Society for Neuroscience and the College on Problems of Drug Dependence and were discussed in a recent review (Spealman et al., 1999).
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↵2 Present address: SRI International, Center for Health Sciences, Policy Division, 333 Ravenswood Ave., Menlo Park, CA 94025.
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↵3 Present address: Dept. of Psychology, Morgan State University, Jenkins Behavioral Science Bldg., Baltimore, MD 21251.
- Abbreviations:
- DA
- dopamine
- FR
- fixed ratio
- FI
- fixed interval
- TO
- time-out
- SKF-81297
- (±)6-chloro-7,8,dihydroxy-1-phenyl-2,3,4,5,-tetrahydro-1H-3-benzazepine hydrobromide
- SKF-82958
- (±)6-chloro-7,8,dihydroxy-3-allyl-1-phenyl-2,3,4,5,-tetrahydro-1H-3-benzazepine hydrobromide
- SKF-83959
- (±)3-methyl-6-chloro-7,8-dihydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine
- SKF-38393
- (±)7–8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride
- ecopipam (SCH 39166)
- (−)-trans-6,7,7α,8,9,13β-hexahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo[d]naptho[2,1-b]azepine
- NPA
- R(−)-propylnorapomorphine hydrochloride
- SDZ-208-911
- N-[(8α)-2,6-dimethylergoline-8-yl]-2,2-dimethylpropanamide
- 7-OH-DPAT
- (±)7-hydroxy-N,N-di-n-propyl-2-aminotetralin hydrobromide
- PD-128,907
- S(+)-(4αR,10βR)-3,4,4α,10β-tetrahydro-4-n-propyl-2H,5H-[1]benzopyrano [4,3-b]1,4-oxazin-9-ol hydrochloride
- flupenthixol
- cis-z-flupenthixol
- eticlopride
- S(−)-eticlopride HCl
- YM-43611
- (S)-N-(1-benzyl-3-pyrrolidinyl)-5-chloro-4-cyclopropylcarbonylamino-2-methoxybenzamide
- UH-232
- cis-(+)-1S,2R-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin maleate
- AJ-76
- (1S,2R)-cis-5-methoxy-1-methyl-2-(n-propylamino)tetralin hydrochloride
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- Received November 30, 1999.
- Accepted May 2, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
