Cocaine-induced convulsions: pharmacological antagonism at serotonergic, muscarinic and sigma receptors.
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.
Ritz
M C
MC
Amethyst Technologies, Inc., Scottsdale, AZ 85257-3773, USA. ritzmc@aol.com
George
F R
FR
D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011976:Receptors, Muscarinic / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects*; D017480:Receptors, sigma / Q000037:antagonists & inhibitors*; D012640:Seizures / Q000139:chemically induced*
D011976:Receptors, Muscarinic; D011985:Receptors, Serotonin; D017480:Receptors, sigma; D003042:Cocaine