LY293558, an AMPA glutamate receptor antagonist, prevents and reverses levodopa-induced motor alterations in parkinsonian rats

To evaluate the possible involvement of glutamate AMPA receptor-mediated me chanisms in levodopa-induced motor fluctuations, we investigated the effect s of LY293558, a competitive AMPA receptor antagonist, on levodopa-induced motor alterations in rats with unilateral 6-OHDA lesion. Acute and chronic administration of LY293558 was studied to evaluate the possible reversion o r prevention of these levodopa effects. In the first set of experiments, ra ts were treated with levodopa (25 mg/kg with benserazide, twice daily, i.p. ) for 22 days and on day 23 LY293558 (5 mg/kg, i.p.) was administered immed iately before levodopa. In the second set of experiments, rats were treated daily for 22 days with levodopa and LY293558 (5 mg/kg, twice daily, i.p.). In the third set of experiments, the effect of LY293558 (5 mg/kg, i.p.) ad ministration on selective dopamine D-1 (SKF38393, 1.5 mg/kg, s.c.) and D-2 agonist (quinpirole, 0.1 mg/kg, i.p.)-induced rotational behavior after dai ly levodopa treatment was studied. The duration of the rotational behavior induced by chronic levodopa decreased by 30% after 22 days. Acute administr ation of LY293558 on day 23 reversed this effect. The group of animals that were chronically treated with levodopa and LY293558 did not show the decre ase in this motor response duration. Chronic levodopa treatment attenuated the rotational response to the D-1 agonist SKF38393 and increased the respo nse to the D-2 agonist quinpirole. LY293558 did not reverse the effect of l evodopa on rotational behavior induced by the D-1 agonist but significantly reduced the rotational response to the D-2 agonist in levodopa-treated ani mals by 40%. Our results demonstrate that an AMPA receptor antagonist rever ses and prevents levodopa-induced motor alterations in parkinsonian rats an d that this effect on motor fluctuations induced by chronic levodopa is pro bably due to a modulation of the indirect output pathway of the basal gangl ia. Synapse 42:40-47, 2001. (C) 2001 Wiley-Liss, Inc.