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, select ively activates mGlu2/3 receptors with EC50 values in the low nanomolar ran ge. 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 foll owing 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.)-elici ted 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. Dose s up to 3 mg/kg p.o. LY379268 were without effect on the rotorod performanc e of rats when measured at 1, 2, 4, 8, and 24 h post-administration. In agr eement 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 L Y379268 (10, 30, or 100 mg/kg p.o.) was absent following 4-day repeated adm inistration of LY379268. In contrast, the potency of LY379268 for the inhib ition of PCP-evoked motor activities was not affected following multiple do sing over a similar period. These results demonstrate that although the red uction of PCP motor activities by LY379268 is maintained after subchronic d osing, tolerance to the motor impairment evoked by the compound occurs, thu s greatly widening the therapeutic index of LY379268.