Abstract
Cholinergic muscarinic systems have been shown to influence dopaminergic function in the central nervous system. In addition, previous studies of benztropine analogs that inhibit dopamine uptake and show antagonism at muscarinic receptors show these drugs to be less effective than cocaine in producing its various prototypic effects such as locomotor stimulation. Because previous pharmacological studies on these topics have used nonselective M1 antagonists, we examined the interactions of preferential M1 muscarinic antagonists and cocaine. Dose-dependent increases in extracellular levels of dopamine in selected brain areas, the nucleus accumbens (NAc) shell and core, and the prefrontal cortex, were produced by cocaine but not by the preferential M1 antagonists telenzepine and trihexyphenidyl. When administered with cocaine, however, both M1 antagonists dose-dependently increased the effects of cocaine on dopamine in the NAc shell, and these effects were selective in that they were not obtained in the NAc core or in the prefrontal cortex. Telenzepine also increased locomotor activity, although the effect was small compared with that of cocaine. The locomotor stimulant effects of trihexyphenidyl, in contrast, approached those of cocaine. Telenzepine attenuated, whereas trihexyphenidyl enhanced the locomotor stimulant effects of cocaine, with neither drug facilitating cocaine-induced stereotypy. The present results indicate that preferential antagonist effects at muscarinic M1 receptors do not uniformly alter all of the effects of cocaine, nor do they explain the differences in effects of cocaine and benztropine analogs, and that the alterations in dopamine levels in the NAc shell do not predict the behavioral effects of the interactions with cocaine.
Footnotes
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This study was supported by the Intramural Research Program, Department of Health and Human Services, National Institute on Drug Abuse, National Institutes of Health.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.118067.
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ABBREVIATIONS: DA, dopamine; NAc, nucleus accumbens; BZT, benztropine; TZP, telenzepine; TXP, trihexyphenidyl; WIN 35,428, 2β-carbomethoxy-3β-(4-fluorophenyl)tropane; PEI, polyethyleneimine; PFCX, prefrontal cortex; AHN 1-055, [4′-4″-difluoro-3α-(diphenylmethoxy)-tropane]; 4′-4″-diCl-BZT, [4′-4″-dichloro-3α-(diphenylmethoxy)-tropane]; 4-Cl-BZT, [4′-chloro-3α-(diphenylmethoxy)-tropane]; ANOVA, analysis of variance; GBR 12909, 1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine; VTA, ventral tegmental area.
- Received December 1, 2006.
- Accepted January 23, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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