Allosteric modulation of GluN2C/GluN2D-containing NMDA receptors bidirectionally modulates dopamine release: implication for Parkinson's disease

Background and PurposeAllosteric modulators of ionotropic receptors and GPCRs might constitute valuable therapeutic tools for intervention in several diseases, including Parkinson's disease (PD). However, the possibility that some of these compounds could alter neurotransmission in health and disease has not been thoroughly examined. Hence, we determined whether CIQ, a positive allosteric modulator of NMDA receptors that contain the GluN2C or GluN2D subunits, modulates dopamine release in the striatum of control mice and of a mouse model of presymptomatic Parkinsonism. Experimental ApproachWe used amperometry to measure, in mouse brain slices containing the dorsal striatum, dopamine release evoked by stimulations that mimicked tonic (single pulses) or phasic (trains) activity. We used control mice and mice with a partial, 6-hydroxydopamine-induced, degeneration of dopaminergic neurons in the substantia nigra. Key ResultsIn control mice, CIQ inhibited tonic dopamine release and induced an initial inhibition followed by a long-lasting increase in phasic release. Pirenzepine, a muscarinic receptor antagonist, blocked the depression of release induced by CIQ, but not the long-lasting potentiation. CIQ also increased action potential firing in striatal cholinergic interneurons. In the partially dopamine-depleted striatum, CIQ induced an inhibition followed by a potentiation of both tonic and phasic release, but did not significantly increase the firing of cholinergic interneurons. Conclusions and ImplicationsCIQ has bidirectional, activity- and ACh-dependent, modulatory effects on dopamine release in the striatum. This study suggests a potentially valuable means to enhance dopamine release in presymptomatic Parkinsonism.