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.

Mechanisms of Acute Cocaine Toxicity

“…Similar effects have been reported for other SERT inhibitors [59]. Serotonin receptor antagonists (5HT2 and 5HT3) decrease the incidence of seizures [60]. As cocaine has a very low affinity for serotonin (5HT) receptors [29] ,the effects of 5HT2 and 5HT3 antagonists cannot be due to inhibition of cocaine binding.…”

“…Rimcazole and BD1008, selective sigma antagonists, attenuate the lethal and epileptogenic effects of cocaine in animal models [65,66]. Older reports have suggested that the sigma receptor agonist SKF-10047attenuates the epileptogenic and lethal effects of cocaine [60,[66][67][68]. While these data are conflicting and it is unclear which sigma receptor subtype is involved, it appears that sigma receptors contribute to the toxic effects of cocaine.…”

“…Cocaine attenuates the methacholine induced reduction in heart rate suggesting that it acts as an antagonist at muscarinic receptors [30], but pirenzepine, an M1 receptor antagonist, decreases the lethality and epileptigenic effects of cocaine in a mouse model [60,71]. These apparently contradictory effects could be explained if cocaine acts as a partial agonist at muscarinic receptors, but the exact effect of cocaine on muscarinic receptors are unclear.…”

Effects of disulfiram and dopamine beta-hydroxylase knockout on cocaine-induced seizures

“…Serotonergic activity modulates seizure activity in response to cocaine and seems to have proconvulsant effects. Selective 5-HT reuptake inhibitors, such as fluoxetine, citalopram, paroxetine and the tricyclic antidepressant imipramine, all facilitate CIS (O'Dell et al, 1999;Ritz and George, 1997), whereas 5-HT 2 receptor antagonists decrease CIS (O'Dell, et al, 1999Ritz and George, 1997;Schechter and Meehan, 1995). Since cocaine is known to inhibit 5-HT transporters (SERT), increases in 5-HT following cocaine administration can lead to accumulation of serotonin in synapses, which in turn can increase seizure activity via 5-HT 2 receptor activation.…”

Effects of UMB24 and (±)-SM 21, putative σ2-preferring antagonists, on behavioral toxic and stimulant effects of cocaine in mice

“…The affinities of these compounds for 5-HT 2 receptors were also examined because antagonists at these sites are capable of attenuating the toxicity of cocaine (Ritz and George, 1997). The affinities of the ligands were measured in homogenates from rat brain minus cerebellum using previously published methods (Matsumoto et al, 1995).…”