The effects of cocaine on cerebral metabolic function in periweanling rats: the roles of serotonergic and dopaminergic uptake blockade

Abstract

This report examines the short-term effects of cocaine exposure during postnatal (PoN) days 11–21 on the metabolic function of major central neuronal systems in the rat. It also examines the effects of inhibition of serotonin and dopamine uptake during this period of development. By comparing the effects of fluoxetine, a serotonin uptake inhibitor, and GBR12909, a dopamine uptake inhibitor, to the effects of cocaine, the contributions of these pharmacologic actions to the neurochemical effects of cocaine were determined. Four groups of rats were injected subcutaneously: cocaine (25 mg/kg), fluoxetine (25 mg/kg), GBR12909 (25 mg/kg) and vehicle-injected. On day 21 all received their final dose of drug or vehicle 20 minutes prior to the deoxyglucose procedure. Glucose utilization in 43 of 56 brain regions selected for analysis showed a main effect of treatment (P ≤ 0.05, ANOVA) and 7 showed significant treatment × gender interactions. Females demonstrated a markedly greater sensitivity to the effects of cocaine than did the males. Both males and females showed a negligible response to fluoxetine treatment. In the female cocaine-treated group, 10 of 13 motor structures, 7 of 12 sensory structures, 10 of 24 limbic structures, 2 of 2 association areas, and 3 of 5 hypothalamic structures demonstrated significantly increased rates of glucose utilization compared to the vehicle-injected group ( P ≤ 1 = 0.05, Dunnett test). In the cocaine-treated males, only 3 of 56 regions were affected. The gender differences in response to GBR12909 were less apparent. In the females, 11 regions showed increased rates of glucose utilization, while in the males 7 regions were stimulated. Fluoxetine produced the smallest overall effect with 2 structures showing increases in metabolism in the females and 2 structures showing decreases in metabolism in the males. The present study therefore suggests at 21 days of age, that inhibition of dopamine uptake makes a more significant contribution to the metabolic effects of cocaine than inhibition of serotonin uptake and that females are more sensitive to the effects of cocaine than males. Furthermore, the sexual dichotomy seen in the long-term effects of cocaine; i.e., females show the greater effect; is also seen at the time of drug administration.