Interaction between metabotropic adenosine A2A and glutamate MGLU5 receptors in parkinsonian like muscle rigidity and tremor

Muscle rigidity and resting tremor are among the cardinal features of Parkinson’s disease (PD). Recently it has been proposed that antagonists of metabotropic adenosine A2A and glutamatergic mGluR5 receptors may offer a new PD therapy. It is known that A2A and mGluR5 receptors form heteromeric complexes and interact with each other. The aim of the present study was to determine whether joint administration of the A2A and the mGluR5 receptor antagonists SCH58261 and MTEP, respectively, synergistically influenced parkinsonian-like muscle rigidity and tremor in rats. Muscle rigidity was induced by haloperidol (Hal, 0.5 mg/kg), and was estimated by a mechanomyographic method (MMG). Parkinsonian- like tremor was induced by tacrine (2.5 mg/kg). The number of both tremulous jaw movements (TJMs), defined as vertical deflections of the lower jaw not directed at any particular stimulus, and bursts of jaw movements (at least 4 TJMs) was assessed. SCH58261 (0.1–1 mg/ kg) only slightly influenced the Hal-induced muscle resistance and EMG activity during both extension and flexion of the hind foot, butdid not change the tacrine-induced TJMs. Administration of MTEP (1 mg/kg) partially decreased the muscle rigidity evoked by haloperidol, but did not affect the tacrine-induced TJMs. Combined treatment with SCH58261 (1 mg/kg) and MTEP (1 mg/kg) synergistically diminished the haloperidol-induced muscle rigidity. Similarly, SCH58261 (3 mg/kg) and MTEP (1 mg/kg) decreased the tacrineinduced TJMs. The present study demonstrates that acute blockade of A2A - and mGluR5 receptors potentiates their beneficial effects in animal models of PD, which makes this pharmacological strategy a promising nondopaminergic therapy in the treatment of motor deficits in PD