Tolerance to the motor impairment, but not to the reversal of PCP-induced motor activities by oral administration of the mGlu2/3 receptor agonist, LY379268

The potent metabotropic glutamate (mGlu) receptor agonist, LY379268, selectively activates mGlu2/3 receptors with EC50 values in the low nanomolar range. We have previously shown in rats that LY379268 reverses phencyclidine (PCP)-induced motor activations (increases in ambulations and fine movements, and decreases in the animals time at rest). Here, we have investigated: (1) the dose-response and time course for this action of LY379268 following oral (p.o.) administration and (2) the therapeutic index in this model following acute versus subchronic (4 days) p.o. dosing. LY379268 (3 mg/kg p.o.) evoked a maximal effect on PCP (5 mg/kg s.c.)-elicited behaviors 4 h post-dosing. At this time point, p.o. LY379268 inhibited the effects on PCP-elicited activities with a similar potency (EDS, values ca 1 mg/kg) to that previously obtained following s.c. administration. Doses up to 3 mg/kg p.o. LY379268 were without effect on the rotorod performance of rats when measured at 1, 2, 4, 8, and 24 h post-administration. In agreement with the peak time-effect on PCP-evoked motor behaviors, 10 mg/kg p.o. LY379268 only significantly impaired rotorod performance at the 4-h time point. Interestingly, acute motor impairment produced by higher doses of LY379268 (10, 30, or 100 mg/kg p.o.) was absent following 4-day repeated administration of LY379268. In contrast, the potency of LY379268 for the inhibition of PCP-evoked motor activities was not affected following multiple dosing over a similar period. These results demonstrate that although the reduction of PCP motor activities by LY379268 is maintained after subchronic dosing, tolerance to the motor impairment evoked by the compound occurs, thus greatly widening the therapeutic index of LY379268.