Effects of muscarinic M1 receptor blockade on cocaine-induced elevations of brain dopamine levels and locomotor behavior in rats.

Full 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.

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Author information

Author/s: Tanda, Gianluigi (G); Ebbs, Aaron L (AL); Kopajtic, Theresa A (TA); Elias, Lyn M (LM); Campbell, Bettye L (BL); Newman, Amy H (AH); Katz, Jonathan L (JL);

Affiliation: Psychobiology, Department of Health and Human Services, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA. gtanda(-atsign-)intra.nida.nih.gov

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Intramural

Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther), published in United States. (Language: eng)

Reference: 2007-Apr; vol 321 (issue 1) : pp 334-44

Dates: Created 2007/03/19; Completed 2007/05/14;

PMID: 17255465, status: MEDLINE (last retrieval date: 12/26/2008)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals
Benztropine - pharmacology
Brain Chemistry - drug effects
Cocaine - pharmacology
Dopamine - metabolism
Dopamine Plasma Membrane Transport Proteins - metabolism
Dopamine Uptake Inhibitors - pharmacology
Male
Microdialysis
Motor Activity - drug effects

Motor Activity - drug effects
Muscarinic Antagonists - pharmacology
Nucleus Accumbens - drug effects; metabolism
Prefrontal Cortex - drug effects; metabolism
Protein Binding
Rats
Rats, Sprague-Dawley
Receptor, Muscarinic M1 - drug effects
Stereotyped Behavior - drug effects
Synaptic Transmission - drug effects

Associated Chemicals: Dopamine Plasma Membrane Transport Proteins (0) ; Dopamine Uptake Inhibitors (0) ; Muscarinic Antagonists (0) ; Receptor, Muscarinic M1 (0) ; Cocaine (50-36-2) ; Dopamine (51-61-6) ; Benztropine (86-13-5)

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