L-701,324, a selective antagonist at the glycine site of the NMDA receptor, counteracts haloperidol-induced muscle rigidity in rats

Rationale: It has recently been suggested that the overactivity of glutamat ergic neurotransmission may contribute to the pathophysiology of Parkinson' s disease. Therefore, a search for new compounds which block glutamatergic receptors and show antiparkinsonian properties in animal models of this dis ease seems to be justified. Objective: The aim of this study was to determi ne whether L-701,324 [7-chloro-4-hydroxy-3(3-phenoxy) phenylquinoline-2-(H) -one], a selective and full antagonist at the glycine site of the NMDA rece ptor, counteracts parkinsonian-like muscle rigidity and catalepsy induced b y haloperidol in rats. Methods: The muscle tone was measured as the resista nce developed to passive flexion and extension of the hind limb. Electromyo graphic (EMG) activity was additionally recorded in the gastrocnemius and t ibialis anterior muscles. Results: L-701,324 (2.5-40 mg/kg IP) dose-depende ntly decreased the muscle tone enhanced by haloperidol (1-5 mg/kg IP). Like wise, the haloperidol-enhanced resting EMG activity and the EMG reflex resp onse to passive movements were diminished by lower and almost abolished by higher doses of L-701,324. However, up to a dose of 20 mg/kg IF, L-701,324 did not influence haloperidol (0.5 mg/kg IP)-induced catalepsy. Moreover, L -701,324 (1.25-5 mg/kg IF) given alone or together with haloperidol (0.5-1 mg/kg IP) disturbed rotarod performance. Gross observation of behaviour ind icated that rats injected with L-701,324 in doses equal to or higher than 5 mg/kg, alone or in combination with haloperidol, were markedly ataxic, i.e . rats showed signs of disturbed balance and loss of control over their hin d limbs. Conclusions: The present study suggests that L-701,324 exhibits a beneficial action in the animal model of parkinsonian rigidity, but not tha t of parkinsonian akinesia. Nonetheless, this compound is not devoid of mot or side-effects.