Cocaine-induced convulsions: pharmacological antagonism at serotonergic, muscarinic and sigma receptors.

Abstract

The concurrent influence of multiple neurotransmitter systems in mediating cocaine-induced convulsions is predicted by the results of previous receptor binding studies. The present results demonstrate that pharmacological manipulations of these predicted neurotransmitter systems alters the occurrence of cocaine-induced convulsions. The 5-HT reuptake inhibitor fluoxetine enhanced the occurrence and severity of convulsions produced by 100 mg/kg (-) cocaine, while the 5-HT2 receptor antagonists cinanserin, ketanserin and pirenperone antagonized cocaine-induced convulsions in a dose-dependent manner. Further, the M1 receptor antagonist pirenzepine antagonized cocaine-induced convulsions, but atropine did not. In addition, both the (+) and (-) stereoisomers of the sigma ligand SKF 10047 significantly attenuated cocaine-induced convulsions. (+)SKF 10047 was more potent than (-)SKF 10047 in this effect, suggesting a stereoselective effect at sigma receptor sites. In constrast, DA and NE neurotransmission do not appear to modulate the proconvulsant effects of cocaine in a specific, dose-dependent manner. Thus, of the CNS binding sites with which cocaine is known to interact, the results are consistent with the conclusion that 5-HT transporters and 5-HT2 receptor sites appear to be direct and primary sites related to cocaine-induced convulsions, while M1 and sigma binding sites appear to play important but secondary and modulatory roles in this response.

• Authors: M C Ritz, F R George
• Journal: Psychopharmacology (Psychopharmacology (Berl)) Vol. 129 Issue 4 Pg. 299-310 (Feb 1997) ISSN: 0033-3158 [Print] Germany
• PMID: 9085399 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Receptors, Muscarinic
• Receptors, Serotonin
• Receptors, sigma
• Cocaine

Topics

• Animals
• Cocaine (pharmacology)
• Dose-Response Relationship, Drug
• Male
• Mice
• Mice, Inbred C57BL
• Receptors, Muscarinic (drug effects)
• Receptors, Serotonin (drug effects)
• Receptors, sigma (antagonists & inhibitors)
• Seizures (chemically induced)