MK-801 subsensitivity following postweaning lead exposure

This study sought to determine whether the reported lead-induced inhibition of binding of the non-competitive NMDA receptor complex antagonist, MK-801, was of sufficient biological strength and relevance to produce changes in MK-801 behavioral sensitivity. Rats were chronically exposed from weaning to levels of 0, 50 or 150 ppm lead (Pb) acetate in drinking water and trained to discriminate the stimulus properties of 0.05 mg/kg MK-801 from saline at 2 months of age using a standard operant food-reinforced drug discrimination paradigm. Following acquisition of the discrimination, various doses of MK-801, of the non-competitive antagonist phencyclidine (PCP), the competitive antagonist CPP, and of NMDA, were substituted for 0.05 mg/kg MK-801 and percent MK-801 lever responding to each determined. Increasing doses of MK-801 and of PCP produced dose-related increases in MK-801 lever responding to levels exceeding 90%, whereas CPP produced levels less than 50 percent. NMDA produced primarily saline lever responding. Pb exposure was associated with MK-801 subsensitivity as indicated by downward and/or right-shifts of the MK-801 dose-effect curve, and by attenuated MK-801 lever responding following an MK-801 washout period. No Pb-related changes in sensitivity to PCP, CPP or NMDA were observed. These data provide in vivo support for the possibility that glutamatergic system changes could be involved in the behavioral toxicity produced by lead exposure.