Abstract
The reinforcing effects of many psychomotor stimulants have been related to increased dopaminergic neurotransmission and stimulation of central nervous system (CNS) dopamine (DA) receptors. Consistent with this notion, some drugs that directly stimulate DA receptors have been found to function as positive reinforcers. The present experiments were designed to examine why some, but not all, D1 receptor agonists can function as reinforcers in rhesus monkeys by comparing behavioral and CNS in vitro measures of potency and efficacy. Seven rhesus monkeys were allowed to self-administer cocaine under a progressive-ratio (PR) schedule until stable responding was established. Various doses of D1 agonists, previously reported to function as positive reinforcers, were then made available for self-administration. Stimulation of cAMP production in rhesus and rat striatal tissue was studied for these compounds and for D1 agonists previously reported not to function as positive reinforcers in monkeys (SKF 38393, SKF 77434 and S(−)-6-BrAPB). Blockade of DA uptake in rat striata was also examined for all compounds. SKF 81297, SKF 82958 and R(+)-6-BrAPB maintained responding under the PR schedule and did not differ significantly in efficacy as positive reinforcers; SKF 81297 was less potent than the other two agonists. SKF 81297, SKF 82958 and R(+)-6-BrAPB stimulated higher levels of cAMP production in rhesus striata than did SKF 38393, SKF 77434 and S(−)-6-BrAPB. In contrast, all compounds blocked DA uptake. Thus, reinforcing efficacy among D1 agonists increases with efficacy in stimulating D1 receptors.
Footnotes
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Send reprint requests to: William. L. Woolverton, Ph.D., Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS 39216-4505.
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↵1 Supported by National Institute on Drug Abuse grants DA-00250 (W.L.W.), DA-10352 (W.L.W.), DA-05616 (M.R.W.) and DA-05312 (L.P.D.). The experiments were conducted in accordance with the Guide for Care and Use of Laboratory Animals from the National Institutes of Health. Experimental protocols were reviewed and approved by the Institutional Animal Care and Use Committees of the University of Chicago, the University of Mississippi Medical Center and the University of Kentucky.
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↵2 Present address: The Scripps Research Institute, Department of Neuropharmacology, La Jolla, CA.
- Abbreviations:
- DA
- dopamine
- PR
- progressive-ratio
- FR
- fixed ratio
- TO
- time-out
- LH
- limited hold
- CNS
- central nervous system
- ANOVA
- analysis of variance
- CI
- confidence interval
- EGTA
- ethyleneglycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid
- HEPES
- N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid
- Received December 23, 1996.
- Accepted June 2, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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