NMDA antagonists block expression of sensitization of amphetamine- and apomorphine-induced stereotypy

We have been studying sensitization of psychostimulant-induced stereotyped behavior in mice using both single and multiple pretreatment paradigms. In the present study, we tested whether NMDA receptor antagonists and an inhibitor of nitric oxide synthesis inhibit expression of sensitization in either of these models. Male CF-1 mice were pretreated with a single dose or with three daily doses of amphetamine (14 mg/kg) or apomorphine (40 mg/kg). Two days following these pretreatments, mice were injected with ((+/-)3-(2-carboxypiperazine-4yl)-propyl-1-phosphonic acid (CPP, 20 mg/kg), dizocilpine maleate (MK-801, 0.1 mg/kg), 7-nitroindazole (25 mg/kg), or vehicle 30 min before receiving amphetamine (7 mg/kg) or apomorphine (3 mg/kg). The stereotyped behavioral response was enhanced in mice pretreated with amphetamine or apomorphine, indicating that sensitization had developed. CPP, MK-801, and 7-nitroindazole prevented the expression of the sensitized stereotyped response induced by either amphetamine or apomorphine in both paradigms. These drugs did not attenuate the stereotypy elicited by amphetamine and apomorphine in drug-naïve mice. The effect of 7-nitroindazole was reversed by pretreatment with 500 mg/kg of L-arginine but not by D-arginine. These results suggest that glutamatergic transmission and subsequent NMDA receptor activation and the production of nitric oxide play a critical role in the expression of the sensitized stereotyped behavioral response elicited by amphetamine or apomorphine.