M1 and M4 muscarinic receptors from hippocampus are positively involved in memory consolidation

Abstract

The muscarinic antagonist scopolamine causes amnesia in rats, both systemically or administered into the hippocampus after training, supporting the involvement of muscarinic receptors (MAChR) in memory. The role of MAChR subtypes was poorly understood in vivo due to the lack of enough selective pharmacological tools. Central M1, M3 and M5 receptors are mainly coupled to the phosphoinositide pathway, while central M2 and M4 receptors couple to the inhibition of stimulated adenylate cyclase (AC).Muscarinic toxins (MTs) from Dendroaspis snakes venom are selective for MAChR subtypes. MT1 and MT2, with affinity order M1M4 other subtypes, behaved as M1 agonists in various preparations. MT3 is highly selective for M4 receptors. These MTs fully antagonised the muscarinic inhibition of FSK‐stimulated hippocampal AC. As these MTs have negligible binding to M2 receptor, the M4 subtype must be responsible for most of the AC inhibition. Pirenzepine, an antagonist with similar affinity for M1 and M4, given into the hippocampus after an inhibitory avoidance task was amnesic. MT1 and MT2 facilitated memory consolidation, corroborating the positive involvement of M1 receptors. At a higher dose of MT2, the facilitation disappeared, suggesting that it was acting at another site, likely blocking M4 receptors. These results strongly support that M4 receptor of the hippocampus, responsible for muscarinic inhibition of AC, positively modulates memory consolidation.