Antiparkinsonian Actions of Blockade of NR2B-Containing NMDA Receptors in the Reserpine-Treated Rat

Current symptomatic treatment for Parkinson's disease is based largely on dopamine-replacing agents. The fact that long-term treatment with these drugs is characterized by many side effects has lead to widespread interest in nondopaminergic therapies. To date, however, it has proved difficult to devise a nondopaminergic therapy with significant antiparkinsonian efficacy when administered as monotherapy. Overactivity of the striatolateral pallidal pathway, the “indirect” striatal output pathway, is thought be responsible for the generation of parkinsonian symptoms. Indeed, it has been suggested that selective reduction in the activity of the “indirect” pathway may be achieved by blockade of NR2B-containing NMDA receptors. In the present study, we demonstrate that selective blockade of NR2B-containing NMDA receptors with the polyamine antagonists ifenprodil and eliprodil causes a significant increase in locomotor activity in the reserpine-treated rat model of Parkinson's disease (30 mg/kg ifenprodil, 221.2±54 mobile counts compared to vehicle, 19.6±6.87,P