Abstract
The present study investigated the pharmacological properties of a piperidine-based novel cocaine analog, namely, (+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylic acid [(+)-CPCA]. Like cocaine, (+)-CPCA inhibited rat synaptosomal dopamine and norepinephrine uptake with high affinity, but was 33-fold less potent than cocaine in inhibiting serotonin uptake. Like cocaine, (+)-CPCA is a locomotor stimulant, although it was less potent and efficacious than cocaine. Importantly, pretreatment with (+)-CPCA dose dependently blocked the locomotor stimulant effects of cocaine in rats. (+)-CPCA completely substituted for cocaine in drug discrimination tests, although it was about 3 times less potent than cocaine. It was also self-administered by rats. Unexpectedly, (+)-CPCA did not enhance cocaine-induced convulsions in mice. As expected from rodent studies, rhesus monkeys readily self-administered (+)-CPCA. However, compared with cocaine, (+)-CPCA showed limited reinforcing properties in rats as assessed by both fixed and progressive ratio intravenous drug self-administration tests. These results collectively suggest that (+)-CPCA has an atypical pharmacological profile having both cocaine-like “agonist” and some cocaine “antagonist” properties. These properties of (+)-CPCA suggest that it may have utility in the treatment of cocaine craving and dependence.
Footnotes
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This work was supported by a grant from the National Institute on Drug Abuse and in part by the National Institute of Mental Health Psychoactive Drug Screening Program (NO1MH80005).
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DOI: 10.1124/jpet.102.046318
- Abbreviations:
- DAT
- dopamine transporter
- SERT
- serotonin transporter
- (+)-CPCA
- (+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylic acid
- 5-HT
- 5-hydroxytryptamine, serotonin
- GBR12909
- 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine
- Received November 1, 2002.
- Accepted December 6, 2002.
- U.S. Government
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