Functional interaction between adenosine A2A and group III metabotropic glutamate receptors to reduce parkinsonian symptoms in rats

Non-dopaminergic drugs acting either on adenosine A2A or metabotropic glutamate (mGlu) receptors reduce motor impairment in animal models of Parkinson's disease (PD), suggesting a possible functional interaction between these receptors to regulate basal ganglia function. The present study therefore tested the behavioural effects of compounds acting selectively on A2A or on specific mGlu receptor subtypes, alone or in combination, in rodent models of PD. Acute administration of the adenosine A2A receptor antagonists CSC or MSX-3 at the highest doses tested (5 and 1.25 mg/kg, respectively) significantly reduces haloperidol-induced catalepsy. Furthermore, the anticataleptic effect of MSX-3 was enhanced by a 3-week treatment. Acute administration of the selective group III mGlu agonist ACPT-I produces potent anticataleptic effects and prolongs time on rotarod of 6-OHDA-lesioned rats. In contrast, acute or chronic administration of MPEP (mGlu5 receptor antagonist) has no anticataleptic action. Furthermore, the acute co-administration of ACPT-I 1 mg/kg, but not 5 mg/kg, with CSC markedly reduces catalepsy. Opposite effects are observed after a 3-week co-administration. The co-administration of ACPT-I with MSX-3 has anticataleptic effects both after acute or chronic treatment. In contrast, acute combination of subthreshold doses of CSC and MPEP has no effect. After a 3-week treatment, however, the combination of CSC and MPEP was found to reduce haloperidol-induced catalepsy. Altogether, these results show for the first time that systemic activation of group III mGlu receptors with ACPT-I provides benefits in parkinsonian rats and underlie a possible interaction with A2A receptors to regulate basal ganglia motor function.