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 I(NMDA) 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 I(NMDA) displayed an onset-offset rate in the order of a second, and was resistant to the presence of the muscarinic antagonist atropine (10 microM) in the extracellular solution, and of G-protein blocker GDP(beta)S (500 microM) and activator GTP(gamma)S (400 microM) 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 microM). 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.
Flores-Hernandez
Jorge
J
Instituto de Fisiologia, Universidad Autonoma de Puebla, Puebla, Mexico.
Salgado
Humberto
H
De La Rosa
Victor
V
Avila-Ruiz
Tania
T
Torres-Ramirez
Oswaldo
O
Lopez-Lopez
Gustavo
G
Atzori
Marco
M
D000109:Acetylcholine / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001303:Auditory Cortex / Q000166:cytology*; D001703:Biophysics; D018678:Cholinergic Agents / Q000494:pharmacology; D004347:Drug Interactions; D004558:Electric Stimulation; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D016202:N-Methylaspartate / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009474:Neurons; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*
D018678:Cholinergic Agents; D018683:Excitatory Amino Acid Agents; D016194:Receptors, N-Methyl-D-Aspartate; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D016202:N-Methylaspartate; D000109:Acetylcholine