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 < 0.001). Additionally, we show that, subsequent to
dopamine depletion, the ability of
ifenprodil to bind to the
polyamine site and inhibit binding of the
NMDA channel blocker [3H]
MK-801 is increased fourfold (IC50 3.7 +/- 0.4 microM compared to vehicle, IC50 14.3 +/- 2.34 microM, P < 0.01). We suggest that
ifenprodil selectively targets the
polyamine site on overactive NR2B-containing
NMDA receptors. Thus, we propose that NR2B-selective
NMDA receptor antagonists may prove useful in the treatment of
Parkinson's disease.