Can ligands of metabotropic glutamate receptors become antiparkinsonian drugs?
Symptoms of Parkinson's disease (akinesia, muscle rigidity and tremor) result from degeneration of dopaminergic nigrostriatal pathway. Furthermore, a shift of dopaminergic-glutamatergic balance towards overactivation of glutamatergic systems exists in this disease. Therefore, drugs which inhibit glutamatergic transmission were expected to have antiparkinsonian impact. Our studies showed that the blockade of the group I mGluRs (mGluR1 and 5) in the striatum decreased catalepsy and muscle rigidity in the haloperidol-induced animal models of parkinsonism, which seemed to be due to inhibition of the indirect striopallidal pathway. On the contrary, systemic injections of mGluR5 antagonists did not infl uence the tacrine-induced tremor and diminished functioning of the nigrostriatal pathway. Moreover, the mGluR1 antagonist strongly enhanced the tremor induced by harmaline. Agonists of groups II and III mGluRs exerted antiparkinsonianlike effects which differed depending on their brain targets. Agonists of the group II seemed to act at the level of the subthalamo-nigral glutamatergic synapses, but not in the striatum, whereas an antiakinetic effect of agonists of group III was strong in the globus pallidus and striatum, but weak or none in the substantia nigra. The above results seem to suggest that because of a wide distribution of mGluRs in the brain, ligands of these receptors may exhibit limited effi ciency as antiparkinsonian drugs in humans.