ABSTRACT
Previous research in our laboratory suggests that serotonin (5-HT) neurotransmission mediates the expression of cocaine-induced convulsions. The role of 5-HT in mediating this toxic effect of cocaine appears to be due to activation of 5-HT(2) receptors, because cocaine-induced convulsions are blocked by the 5-HT(2) antagonists cinanserin, ketanserin, and pirenperone. The present study utilized a number of compounds that display a high affinity for 5-HT(2) receptors to further examine the role of these sites in mediating this toxic effect of cocaine. Cocaine-induced convulsions were observed following pretreatment with various doses of the following 5-HT(2) antagonists: mianserin, metergoline, MDL 11939, and methiothepin. In addition, 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine (NAN 190) was tested to examine the influence of 5-HT(1) sites and the agonist compound 1-(3-triflurormethylphenyl)piperazine (TFMPP) was examined to further explore the role of 5-HT(1) and 5-HT(2) sites. Each 5-HT(2) antagonist attenuated cocaine-induced convulsions. Conversely, NAN 190 did not alter this toxic effect of cocaine. In addition, TFMPP significantly potentiated cocaine-induced convulsions. The results from this study support the hypothesis that 5-HT neurotransmission, acting primarily at 5-HT(2) receptors, plays an important role in mediating cocaine-induced convulsions.
Subject(s)
Cocaine/toxicity , Dopamine Uptake Inhibitors/toxicity , Receptors, Serotonin/physiology , Seizures/chemically induced , Serotonin Antagonists/pharmacology , Animals , Behavior, Animal/drug effects , Cocaine/antagonists & inhibitors , Dopamine Uptake Inhibitors/antagonists & inhibitors , Dose-Response Relationship, Drug , Male , Mice , Mice, Inbred C57BL , Receptor, Serotonin, 5-HT2C , Receptors, Serotonin/drug effects , Receptors, Serotonin, 5-HT1 , Seizures/physiopathology , Serotonin Receptor Agonists/pharmacologyABSTRACT
RATIONALE: C57BL/6ByJ (6ByJ) and C57BL/6J (6J) mice differ in their sensitivity to cocaine-induced convulsions, with CD(50) values being 100 and 70 mg/kg, respectively. This genetic sensitivity to cocaine-induced convulsions is probably related to 5-HT(2) receptors, since the density of these sites and the concentration of 5-HT(2) antagonists required to block cocaine-induced convulsions is lower in 6J mice relative to 6ByJ mice. OBJECTIVE: Although 5-HT(2) receptors appear to play a role in mediating genetic sensitivity to cocaine-induced convulsions, the role of 5-HT(2) receptor subtypes in this effect of cocaine has not been examined. METHODS: The present study compared the effects of the preferential 5-HT(2C) agonists m-chlorophenylpiperazine (mCPP) and 6-chloro-2-(1-piperazinyl)pyrazine (MK212) on cocaine-induced convulsions in 6ByJ and 6J mice. General activity was also measured following pretreatment with mCPP and MK212. RESULTS: Both mCPP and MK212 potentiated cocaine-induced convulsions and the effect of these agonists was more robust in 6ByJ mice relative to 6J mice. CONCLUSION: The findings from this study support previous research suggesting that 5-HT(2) receptors play a role in mediating cocaine-induced convulsions, and extend previous research by suggesting that the 5-HT(2C) receptor subtype mediates cocaine-induced convulsions and genetic sensitivity to this toxic effect of cocaine.
