Prenatally malnourished female but not male rats show increased sensitivity to MK-801 in a differential reinforcement of low rates task

A reduced behavioral sensitivity to drugs acting on central GABAergic, serotonergic, opioid and cholinergic systems has previously been identified in predominantly male malnourished animals. The present study sought to compare the effects of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 on responding maintained by a differential reinforcement of low rates (DRL-18s) operant schedule in two groups of rats with different prenatal nutritional histories (well-nourished and protein restricted). The schedule required that the rats space their responses at least 18 s apart in order to obtain food reinforcement (timing behavior). After training to a stable high proficiency, MK-801 was administered to female rats (Experiment 1) at doses of 0 (saline), 0.004, 0.008, 0.016, 0.024 or 0.032 mg/kg (doses expressed as the free-base). MK-801 produced dose-dependent decreases in the percentage efficiency of responding and the number of rewarded responses, with dose-dependent increases in the number of responses emitted. Prenatal malnutrition significantly shifted the inter-response time (IRT) curve to the left, relative to that of the well-nourished controls, leading to a significantly lower efficiency and a lower number of reinforcers, at an MK-801 dose of 0.016 mg/kg. In Experiment 2, the effect of MK-801 on DRL performance was compared between male and female rats after prenatal malnutrition. In general, females proved more sensitive to MK-801 than males. Consistent with Experiment 1, a significantly greater drug impairment was observed in prenatally malnourished females compared with well-nourished females, albeit at a slightly higher dose (0.032 mg/kg). Prenatal malnutrition did not alter the drug response in male rats. These findings suggest that the behavioral response to NMDA blockade is augmented in adult female, but not male, rats after prenatal malnutrition.