Abstract
Serotonergic transmission has been suggested to modulate the effects of cocaine. However, the specific receptors and brain structures underlying this phenomenon have not been identified. To test the possible contribution of the 5-hydroxytryptamine1B(5-HT1B) receptor, we studied the induction of the immediate-early gene c-fos elicited by cocaine in knockout mice lacking this receptor. 5-HT1B knockout mice display a markedly reduced effect of cocaine on c-fosinduction in different brain structures, most notably in the striatum. In addition, the administration to wild-type mice of the 5-HT1B receptor agonist RU24969 results in a striatal induction of c-fos expression very similar to that induced by cocaine in its time course, cellular and anatomical distribution, and pharmacology. Here, we also report the ability of a 5-HT1D receptor antagonist, GR127935, to antagonize 5-HT1B receptors in vivo. Finally, when administered to wild-type mice, GR127935 reduces the increase in striatal c-fos expression elicited by cocaine. These converging lines of evidence obtained with the knockout mice and 5-HT1B/1D antagonist indicate that cocaine acts as an indirect agonist of 5-HT1B receptors in vivoand demonstrate that activation of 5-HT1B receptors contributes to the cellular responses elicited by cocaine.
Footnotes
- Received December 13, 1996.
- Accepted January 28, 1997.
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Send reprint requests to: Dr. René Hen, Center for Neurobiology & Behavior, College of Physicians and Surgeons, Columbia University, 722 West 168th Street, P.I. Annex Building, Room 725, New York, NY 10032. E-mail: rh95{at}columbia.edu
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↵1 Current affiliation: Centre Nationale de Recherche Scientifique URA339, Laboratoire de Neurosciences Comportamentales et Cognitives, Universite de Bordeaux I, 33405 France.
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This work was supported by National Institute of Drug Abuse Grant DA09862 (R.H.), Bristol Myers Squibb Unrestricted Neuroscience Award (R.H.), European Economic Community (BIO2CT930179) (R.H., L.S.), and NATO Grant CRG940753 (R.H., L.S.). J.J.L. is the recipient of a fellowship from the Ministry of Science and Education of Spain.
- The American Society for Pharmacology and Experimental Therapeutics
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