M3 Muscarinic Receptor‐Mediated Enhancement of NMDA‐Evoked Adenosine Release in Rat Cortical Slices In Vitro

Abstract

Acetylcholine plays an important role in cortical arousal. Adenosine is released during increased metabolism and has been suggested to be a sleep-promoting factor. To understand the interaction of acetylcholine and adenosine in regulating cortical excitability, we examined the effect of carbachol on NMDA-evoked adenosine release and identified the muscarinic receptor subtype that mediated this effect in adult rat cortical slices in vitro. Carbachol (to 300~M) alone did not affect the basal release of adenosine. However, carbachol (100 1sM) induced a 253% increase in NMDA (20 1iM) -evoked adenosine release in the presence of Mg 2~.In the absence of Mg2~,carbachol's potentiating effect was less (60% increase). The nonselective muscarinic antagonist atropine (1.5 j.sM) blocked the facilitatory effect of carbachol on NMDA-evoked adenosine release, and this was mimicked by the M3-selective antagonist 4-diphenylacetoxy-N-methylpiperidine (1 jIM). Neither an Mi-selective dose of pirenzepine (50 nM) nor the M2-selective antagonist methoctramine (1 tiM) affected carbachol's action on NMDA-evoked adenosine release. Carbachol had no effect on adenosine release evoked by a-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA). These results suggest that acetylcholine does not affect basal adenosine release but enhances NMDA receptor-mediated evoked adenosine release by acting at M3 receptors in the cortex. This interaction may have a role in regulating cortical neuronal excitability on a long-term basis.

M1 Receptors Mediate Cholinergic Modulation of Excitability in Neocortical Pyramidal Neurons

“…However, little is known about M3 receptor function in the cortex (but see Semba and White, 1997). Our results demonstrate a role for M3 receptors in regulating the output of cortical pyramidal neurons via modulation of the conductances underlying the AHP.…”

N-Methyl-d-aspartate Receptors Mediate the Phosphorylation and Desensitization of Muscarinic Receptors in Cerebellar Granule Neurons

“…Furthermore, muscarinic receptor subtypes are among a group of GPCRs that are known to regulate NMDA function through a number of mechanisms (16, 24–27). Hence, CG neurons are an ideal native cell type to test the possibility that NMDA receptors might cross-talk with GPCRs.…”

“…Previous studies have determined that muscarinic receptors regulate both NMDA receptor function and contribute to LTP and LTD (16, 24–27). Here we demonstrate that the NMDA receptor-mediated activation of CamKII results in the phosphorylation of the M 3 -muscarinic receptor and subsequent uncoupling of the receptor from the G q/11 /phosphoinositide pathway.…”