Effect of muscarinic cholinergic drugs on ischemia-induced decreases in glucose uptake and CA1 field potentials in rat hippocampus slices

To clarify the role of muscarinic acetylcholinc receptors in the hypoxia/ hypoglycemia (ischemia)-induced functional deficit in hippocampal neurons, we examined the effect of cholinergic drugs on ischemia-induced impairments of glucose uptake and CA1 field potentials in hippocampus slices. Muscarinic receptors were subdivided into M₁ (high affinity for pirenzepine) and M₁ (low affinity for pirenzcpine) subtypes. The M₁ receptor subtype is coupled to an increase in phosphoinositide hydrolysis and the M₂ receptor subtype is associated with inhibition of adenylate cyclase. The greater potency of carbachol in stimulating phosphoinositide hydrolysis resulted in exacerbated ischemia-induced deficits. Treatment with the muscarinic receptor antagonists scopolamine and pircnzepine (M₁ receptor-selective antagonist) had a strong dose-dependent protective effect against ischemia-induced deficits. Oxotremorine and McN-A-343, weak stimulators of phosphoinositide hydrolysis and strong inhibitors of adenylate cyclase, had a weak neuroprotective action against ischemia-induced deficits. These results suggest that stimulation of M₁ musarinic receptors coupled with an increase in phosphoinositide hydrolysis may play a facilatory role in ischemia-induced deficits. Stimulation of M₂ muscarinic receptors may play an inhibitory role in ischemia-induced neuronal deficits.