MK-801 DIFFERENTIALLY AFFECTS DOPAMINE D1 AND D2 RECEPTOR AGONIST-INDUCED BEHAVIORAL TOLERANCE AND DESENSITIZATION

In this study we explored the effects of repeated MK-801 (0.10 mg/kg) treatment on rotation in rats with unilateral forebrain dopamine deple tions. Daily injections of MK-801 across a 13-day period produced mild ipsilateral rotation which did not change significantly across days c ompared to daily injections of vehicle. Rats given repeated cotreatmen t of MK-801 with the selective D1 receptor agonist, A-85653 (0.06 mg/k g), developed response sensitization rather than the behavioral tolera nce that was seen in rats given repeated vehicle + A-85653 injections, However, MK-801 + A-85653 treated rats did demonstrate behavioral tol erance after an acute vehicle + A-85653 challenge, and the behavioral subsensitivity of rats given repeated vehicle + A-85653 injections rev erted to normal in response to an acute MK-801 + A-85653 challenge. Th us, MK-801 blocked the expression but not the development of D1-agonis t induced behavioral tolerance. MK-801 treatment also enhanced striata l c-fos expression produced by A-85653 but only if MK-801 were given i n combination with A-85653 2 h prior to sacrifice; prior daily treatme nt with MK-801 had no carry-over effect. In contrast to its effects on D1 agonist induced rotation, MK-801 cotreatment inhibited the robust contralateral rotation produced by repeated treatment with the D2/D3 a gonist, quinpirole (0.15 mg/kg), and blocked both the development and expression of behavioral supersensitivity compared to rats treated wit h quinpirole alone. These results demonstrate differential effects of repeated MK-801 treatment on the development and expression of D1 and D2/D3 agonist induced response tolerance and sensitization, respective ly.