Clozapine protection against gestational cocaine-induced neurochemical abnormalities

Abstract

Clozapine was found to be effective in attenuating cocaine-induced neurochemical effects. We investigate whether clozapine influences in utero cocaine exposure-induced changes in striatal dopamine levels and cortical N-methyl-D-aspartate (NMDA) receptor density in mouse and rat brains. Pregnant mice or rats were injected with cocaine (5 or 10 mg/kg intraperitoneally) or saline every 24 h throughout gestation and continued for 6 weeks following the delivery. Striatal dopamine levels measured by high-pressure liquid chromatography were found to decrease 24 to 33% in gestational cocaine exposed between the ages of 3 to 15 days, but not in 42-day-old pups. The cortical NMDA receptor densities assessed either in the presence of 100 microM glutamate or 30 microM glycine were significantly increased in 15-day-old gestational cocaine-exposed rats. Simultaneous daily administration of 3 mg/kg clozapine with 5 mg/kg cocaine to pregnant mice protected against the decrease in striatal dopamine levels or an increase in the concentration of NMDA receptor measured in the presence of 100 microM glutamate in 15-day-old pups. Clozapine did not affect striatal dopamine levels by itself or when coadministered with cocaine in 42-day-old pups. The results show gestational cocaine may induce neurochemical abnormalities in brain exhibited as an increased glutamate NMDA receptor density together with a decreased striatal dopamine level. These effects of gestational cocaine exposure may be prevented by simultaneous administration of clozapine. Thus clozapine, which is a partial agonist at the NMDA receptor, may be of value in protecting against gestational cocaine-induced adverse effects in the brain.