Carbachol-evoked suppression of excitatory neurotransmission in guinea-pig olfactory cortex slices is unlikely to involve an M4-muscarinic receptor subtype.

Depression of the electrically-evoked surface-negative field potential (N-Wave) by bath-superfusion of carbachol was measured in guinea-pig olfactory cortex slices maintained in vitro. The possibility that this response, previously proposed to be mediated via a presynaptic M1: muscarinic receptor, might in fact be due to M4 receptor activation, was investigated by testing the effectiveness of himbacine (a proposed M4-selective antagonist) on our cortical preparation. Himbacine (100 nM-1 microM) had no effect on the N-wave potential alone, but it induced a clear competitive-type inhibition of carbachol effects. Schild plot analysis (regression slope constrained to unity) of pooled data yielded a pA2 value of 7.2 for this antagonist (n = 7 slices). This value accords more with that expected for the interaction of himbacine with M1 receptors (approximately 7.2) than with functionally expressed M4 receptors (approximately 8.5-8.5). We therefore conclude that M4-type muscarinic receptors are unlikely to be involved in mediating this presynaptic carbachol response.