N-Methyl-D-aspartate antagonists stimulate locomotor activity in monoamine depleted rats: Implications for the therapy of Parkinson’s disease

Abstract

Recent experimental evidence suggests that the subthalamic and pallidal projections in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated monkeys are abnormally active. In addition, immunocytochemical and electrophysiological studies have shown that the subthalamic nucleus receives a glutamatergic cortical input and subthalamic neurons projecting to the internal pallidal segment (GPi) themselves are glutamatergic. On the basis of these findings we have hypothesized that glutamate antagonists may be beneficial in the therapy of Parkinson’s disease. To test the validity of this hypothesis in a rodent model of Parkinson’s disease we subjected rats to reserpine (5 mg/kg, i.p.; 24 h) and α-methyl-p-tyrosine (250 mg/kg, i.p.; 3.5 h) treatment and tested whether glutamate antagonists, MK-801 (5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate) (0.39–6.25 mg/kg, i.p.), a non-competitive antagonist at the N-methyl-D-aspartate (NMDA) receptor subtype and CPP (3-((±)-2-carboxypiperazin-4-yl)-propyl-1-phosphonate) (0.39–6.25 mg/kg, i.p.), a competitive NMDA antagonist, stimulate locomotor activity. The results show that MK-801 dose-dependently stimulates locomotor activity in monoamine depleted rats and markedly potentiates the action of L-DOPA. CPP also showed stimulatory effects, however its effect was less than MK-801. These observations support the notion that antagonism at NMDA receptors restores locomotion in monoamine depleted animals and raises hopes that adjuvant therapy with NMDA antagonists might improve therapy of patients suffering from Parkinson’s disease.