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 depletions. Daily injections of MK-801 across a 13-day period produced mild ipsilateral rotation which did not change significantly across days compared to daily injections of vehicle. Rats given repeated cotreatment of MK-801 with the selective D1 receptor agonist, A-85653 (0.06 mg/kg), developed response sensitization rather than the behavioral tolerance that was seen in rats given repeated vehicle+A-85653 injections. However, MK-801+A-85653 treated rats did demonstrate behavioral tolerance after an acute vehicle+A-85653 challenge, and the behavioral subsensitivity of rats given repeated vehicle+A-85653 injections reverted to normal in response to an acute MK-801+A-85653 challenge. Thus, MK-801 blocked the expression but not the development of D1-agonist induced behavioral tolerance. MK-801 treatment also enhanced striatal c-fos expression produced by A-85653 but only if MK-801 were given in combination with A-85653 2 h prior to sacrifice; prior daily treatment 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 agonist, quinpirole (0.15 mg/kg), and blocked both the development and expression of behavioral supersensitivity compared to rats treated with 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, respectively.