NMDA receptor blockade reverses motor response alterations induced by levodopa.

Motor fluctuations that ultimately complicate the response of most parkinsonian patients to levodopa therapy might represent a form of behavioral or neuronal plasticity. Since various forms of neuronal plasticity appear to be mediated by glutamate transmission through the N-methyl-D-aspartate (NMDA) receptor, the effect of NMDA receptor blockade on the development of alterations in the motor response to chronic levodopa was evaluated in hemiparkinsonian rats. Repeated levodopa administration decreased rotational behavior induced by a D1 dopamine receptor agonist, increased D2 agonist-induced rotation and progressively reduced the duration of the motor response to levodopa itself. Acute pretreatment with the noncompetitive NMDA antagonist MK-801 completely reversed all these changes. These findings suggest that NMDA receptor-mediated mechanisms contribute to the behavioral plasticity associated with chronic levodopa treatment and that NMDA antagonists might be effective in reversing the motor response complications of the long-term levodopa therapy.