Cholinergic Direct Inhibition of N-Methyl-D Aspartate Receptor-Mediated Currents in the Rat Neocortex

Acetylcholine (ACh) and N-methyl-D aspartate receptors (NMDARs) interact in the regulation of multiple important brain functions. NMDAR activation is indirectly modulated by ACh through the activation of muscarinic or nicotinic receptors. Scant information is available on whether ACh directly interacts with the NMDAR. By using a cortical brain slice preparation we found that the application of ACh and of other drugs acting on muscarinic or nicotinic receptors induces an acute and reversible reduction of NMDAR-mediated currents (I-NMDA), ranging from 20 to 90% of the control amplitude. The reduction displayed similar features in synaptic INMDA in brain slices, as well as in currents evoked by NMDA application in brain slices or from acutely dissociated cortical cells, demonstrating its postsynaptic nature. The cholinergic inhibition Of INMDA displayed an onset-offset rate in the order of a second, and was resistant to the presence of the muscarinic antagonist atropine (10 mu M) in the extracellular solution, and of G-protein blocker GDP(beta)S (500 mu M) and activator GTP(gamma)S (400 mu M) in the intracellular solution, indicating that it was not G-protein dependent. Recording at depolarized or hyperpolarized holding voltages reduced NMDAR-mediated currents to similar extents, suggesting that the inhibition was voltage-independent, whereas the reduction was markedly more pronounced in the presence of glycine (20 mu M). A detailed analysis of the effects of tubocurarine suggested that at least this drug interfered with glycine-dependent NMDAR-activity. We conclude that NMDAR-mediated current scan be inhibited directly by cholinergic drugs, possibly by direct interaction within one or more subunits of the NMDAR. Our results could supply a new interpretation to previous studies on the role of ACh at the glutamatergic synapse. Synapse 63:308-318, 2009. (c) 2009 Wiley-Liss, Inc.