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 inhib itor of nitric oxide synthesis inhibit expression of sensitization in eithe r of these models. Male CF-1 mice were pretreated with a single dose or wit h three daily doses of amphetamine (14 mg/kg) or apomorphine (40 mg/kg). Tw o days following these pretreatments, mice were injected with (+/-)3-(2-car boxypiperazine- 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 stereo typed behavioral response was enhanced in mice pretreated with amphetamine or apomorphine, indicating that sensitization had developed. CPP, MK-801, a nd 7-nitroindazole prevented the expression of the sensitized stereotyped r esponse induced by either amphetamine or apomorphine in both paradigms. The se drugs did not attenuate the stereotypy elicited by amphetamine and apomo rphine in drug-naive mice. The effect of 7-nitroindazole was reversed by pr etreatment with 500 mg/kg of L-arginine but not by D-arginine. These result s suggest that glutamatergic transmission and subsequent NMDA receptor acti vation and the production of nitric oxide play a critical role in the expre ssion of the sensitized stereotyped behavioral response elicited by ampheta mine or apomorphine. (C) 2000 Elsevier Science Inc. All rights reserved.