Muscarinic depression of excitatory synaptic transmission mediated by the presynaptic M3 receptors in the rat neostriatum.

The effect of carbachol on the excitatory synaptic transmission was studied in rat neostriatal neurons using intracellular and whole-cell voltage clamp-recording methods. Depolarizing excitatory postsynaptic potentials (EPSPs) were evoked by cortical stimulation. Superfusion of carbachol (0.01-3 microM) reversibly decreases the EPSP amplitude in a concentration-dependent manner and with an estimated IC50 of 0.3 microM. While, neither the N-methyl-D-aspartate (NMDA, 100 microM)- nor (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA, 100 microM)-induced response was affected by carbachol (0.1 microM). In addition, the inhibitory effect induced by carbachol at a low concentration of 0.1 microM was attenuated by 4-diphenylacetoxy-N,N-methyl-piperidine (4-DAMP), a selective M3 muscarinic receptor antagonist. However, other muscarinic subtype (M1 or M2) antagonists could also block the inhibitory effect by carbachol 0.1 microM. The rank order of antagonist potency was: 4-DAMP (M3 antagonist) > methoctramine (M2 antagonist) > pirenzepine (M1 antagonist). Based on these findings, we conclude that carbachol at a low concentration (< or = 0.1 microM) reduced the excitatory response of neostriatal neurons following cortical stimulation via presynaptic M3 muscarinic receptors located on the terminals of corticostriatal neurons.