Cocaine-induced seizures and lethality appear to be associated with distinct central nervous system binding sites

Cocaine use and abuse has increasingly been associated with toxic consequences such as seizures and death. This report describes an assessment of the relationship between these toxic effects and multiple cocaine binding sites in the brain. The results suggest that serotonin transporters may be associated with seizures induced by acute injections of cocaine and related drugs. Indeed, drug potency for binding at this site alone accounted for 78% of the variance (r = 0.88) in the potency of cocaine and related compounds for producing seizures. However, binding of cocaine-like drugs at sigma receptors or muscarinic M1 or M2 cholinergic receptors may attenuate the seizurgenic properties of these compounds. In contrast, dopamine transporters appear to be associated with lethality induced by cocaine and related drugs, with drug potency for binding at this site accounting for 56% of the variance (r = 0.75) in the potency of cocaine and related compounds for producing death. However, binding of cocaine-like drugs at muscarinic M1 and sigma receptors also appears to be significantly related to cocaine-induced lethality, with binding at these sites accounting for either an additional 31 or 27%, respectively, of the variance in potencies of cocaine and related drugs to produce death. These findings suggest that, although seizure initiation may depend primarily on affinity of cocaine and related compounds for binding sites associated with the serotonin transporter, the seizure-inducing properties of cocaine may ultimately depend on a final summation of its effects not only on serotonergic systems, but on muscarinic and sigma neuronal systems as well. Likewise, although apparently mediated by relatively distinct neuronal mechanisms, the lethal effects of cocaine and related compounds may depend on an interaction of effects at dopaminergic, muscarinic M1 and sigma receptor sites.