Abstract
Drugs that block dopamine uptake often function as positive reinforcers but can differ along the dimension of strength or effectiveness as a positive reinforcer. The present study was designed to examine pharmacological mechanisms that might contribute to differences in reinforcing strength between the piperidine-based cocaine analog (+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3-α-carboxylate [(+)-CPCA] and cocaine. Drugs were made available to rhesus monkeys (n = 5) for i.v. self-administration under a progressive ratio schedule. Both compounds maintained responding with sigmoidal or biphasic dose-response functions (0.1–1.0 mg/kg/injection). (+)-CPCA was one-fourth as potent as cocaine and maintained fewer injections per session, at maximum. For in vitro binding in monkey brain tissue, (+)-CPCA was about one-half as potent as cocaine at the dopamine transporter (DAT), and the two compounds had similar affinities at the norepinephrine transporter. (+)-CPCA was less than 1/10 as potent as cocaine at the serotonin transporter. In ex vivo binding in rat striatum, occupancy of the DAT increased directly with dose to a maximum of approximately 80% for both compounds, and (+)-CPCA was about one-fourth as potent as cocaine. Ex vivo DAT occupancy was significantly higher for cocaine than (+)-CPCA at 2 min after injection but similar at other times. Thus, the primary differences between these compounds were in serotonin transporter affinity and the kinetics of DAT binding. These results suggest that (+)-CPCA is a weaker positive reinforcer than cocaine because it has a slower onset of action over the first few minutes after i.v. injection.
Footnotes
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This research was supported by National Institute on Drub Abuse Grants DA10352, DA00161 (to W.L.W.), MHAG02031 (to G.A.O.), and DA11548 (to A.K.). The data were presented at the 2002 meeting of the American Society of Pharmacology and Experimental Therapeutics, New Orleans, LA.
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DOI: 10.1124/jpet.102.037812
- Abbreviations:
- DAT
- dopamine transporter
- DA
- dopamine
- (+)-CPCA
- (+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3-α-carboxylate
- LH
- limited hold
- TO
- time-out
- 5-HT
- 5-hydroxytryptamine
- CFT
- 2β-carbomethoxy-3β-(4-fluorophenyl)tropane)
- CI
- confidence interval
- S/C
- striatal/cerebellar ratio
- inj
- injection
- GBR 12909
- 1-[2-[bis(4-fluorophenyl)methoxy]ethy]-4-(3-phenylpropyl)piperazine
- Received April 24, 2002.
- Accepted May 29, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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