Chronic cocaine disruption of estrous cyclicity in the rat: Dose-dependent effects

The effects of cocaine on cyclic reproductive function in females remain largely unknown. In this study, we sought to define the range of doses of cocaine effective in disrupting estrous cyclicity and inhibiting ovulation. Estrous cyclicity was monitored daily by vaginal cytology. Group 1 consisted of rats receiving no treatment. Group 2 consisted of rats injected daily with saline s.c. Groups 3 to 6 consisted of rats injected with 1, 5, 10 and 20 mg/kg/day of cocaine HCl s.c., respectively. Group 7 consisted of rats that were food-restricted to allow weight gains comparable to those of group 6. Our results indicate a dose- dependent effect of cocaine on estrous cyclicity with an estimated IC₅₀ of 8.5 mg/kg/day (i.e., the dose of cocaine required to inhibit the number of proestrus:estrus events per 3- week period of analysis by 50%). Over 50% of the rats with cycle disruption on 10 mg/kg/day of cocaine, but almost none of those with cycle disruption on 20 mg/kg/day, returned to normal cyclic patterns after cessation of cocaine treatment. Serum luteinizing hormone levels were reduced 53 and 74% by 10 and 20 mg/kg/day of cocaine, respectively, with an IC₅₀ of 8.9 mg/kg/day. In contrast, cocaine had no significant effect at any of the tested dosages on serum follicle-stimulating hormone or prolactin levels. Ovulation rates were significantly reduced at both 10 and 20 mg/kg/day of cocaine (IC₅₀ = 11 mg/kg/day of cocaine). These data demonstrate that the effects of cocaine to disrupt cyclic reproductive function, including circulating gonadotropin levels, estrous cyclicity and rates of ovulation in rats, is dose dependent and, at higher doses, may be irreversible in some animals.