M3 MUSCARINIC RECEPTOR-MEDIATED ENHANCEMENT OF NMDA-EVOKED ADENOSINE RELEASE IN RAT CORTICAL SLICES IN-VITRO

Acetylcholine plays an important role in cortical arousal. Adenosine i s 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 ef fect of carbachol on NMDA-evoked adenosine release and identified the muscarinic receptor subtype that mediated this effect in adult rat: co rtical slices in vitro. Carbachol (to 300 mu M) alone did not affect t he basal release of adenosine. However, carbachol (100 mu M) induced a 253% increase in NMDA (20 mu M)-evoked adenosine release in the prese nce of Mg2+. In the absence of Mg2+, carbachol's potentiating effect w as less (60% increase). The nonselective muscarinic antagonist atropin e (1.5 mu M) blocked the facilitatory effect of carbachol on NMDA-evok ed adenosine release, and this was mimicked by the M3-selective antago nist 4-diphenylacetoxy-N-methylpiperidine (1 mu M). Neither an M1-sele ctive dose of pirenzepine (50 nM) nor the M2-selective antagonist meth octramine (1 mu M) affected carbachol's action on NMDA-evoked adenosin e release, Carbachol had no effect on adenosine release evoked by pha- amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA). These results s uggest 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 regula ting cortical neuronal excitability on a long-term basis.