Sexual differentiation of the rat brain is affected by certain compounds administered during the neonatal period. We evaluated the effects of exposure to THC during the critical period of sexual differentiation of the female rat brain on postpubertal estrous cycles and brain neurotransmitter levels. Newborn female rats were injected either with vehicle (oil) or with different doses of THC (0.38; 1.9 or 3.8 mg/100 g) subcutaneously during the first 5 days after birth. The rats were examined daily by vaginal lavage smears from 3 to 10 months of life for phases of estrous cyclicity. The animals were then sacrificed and the anterior hypothalamus preoptic area (AHPOA) and medial basal hypothalami (MBH) were collected, processed and the methionine-enkephalin (met-enkephalin), β-endorphin-like immunoreactivity (β-end LI), LHRH and substance-P were measured by radioimmunoassays. In addition, serum LH and prolactin levels were measured by radioimmunoassay. Compared with the control rats, the rats perinatally exposed to THC exhibited either constant metestrus diestrus type vaginal smears or irregular estrous cycles. In the THC-treated animals, the met-enkephalin and β-end LI levels were lower in the AHPOA and higher in the MBH. The LHRH levels of THC-treated rats were significantly lower in the MBH. The substance-P levels were significantly lower in the AHPOA of THC treated animals. In the THC-treated rats, serum LH was low but, the prolactin levels were not significantly different from the control animals. Results indicate that perinatal exposure to THC has long-lasting inhibitory effects on postpuberal reproductive function, perhaps by permanently altering the normal functional associations of those neuronal groups in the diencephalon concerned with the regulation of gonadotrophin secreti