Cocaine toxicity: genetic evidence suggests different mechanisms for cocaine-induced seizures and lethality

Abstract

While low doses of cocaine have been shown to decrease locomotor activity, and moderate doses produce marked increases in locomotor activity, high doses commonly produce seizures and, eventually, death. However, the biological mechanisms associated with cocaine-related death, as well as the contribution of seizure activity to death, are poorly understood. This study examined the effects of a broad range of cocaine doses on acute occurrence of seizures and death in LS/Ibg (LS) and SS/Ibg (SS) mice. Large differences in sensitivity to cocaine-induced seizures were seen, with ED₅₀ values being 41.7 and 80.9 mg/kg for the SS and LS mice, respectively. Conversely, no significant differences in cocaine LD₅₀ values were found, being 100.7 and 107.2 mg/kg for the SS and LS mice, respectively. That these lines of mice differ substantially in convulsant responses to cocaine, but show no difference in lethal response to this drug, supports the conclusion that cocaine causes death by mechanisms distinct from those which contribute to seizures. The distinction between cocaine-induced seizures and lethality in these lines may prove useful in elucidating the underlying mechanisms of these traits. In a subsequent study, the incidence of seizures in F₁ and F₂ generation mice from hybrid matings of LS and SS parents was not consistent with a single gene hypothesis, suggesting that multiple genes and receptors mediate seizurgenic responses to cocaine. Further, albino mice from the F₂ generation did not show a significantly different incidence of seizures than non-albino mice, indicating that of the genes contributing to seizures following cocaine, none appear to be closely associated with the albino locus on mouse chromosome seven.