Two concentration-dependent effects of the muscarinic agonist carbachol (CCh) were characterized in submerged slices of rat hippocampus using extracellular recordings of excitatory postsynaptic potentials (EPSPs): muscarinic long-term potentiation (LTP(m)) and depression. 2. LTP(m) of the EPSP slope was seen following long exposure (20 min) of the slice to low concentrations of CCh (0.2-0.5 microM). This LTP(m) was not accompanied by a change in the size of the afferent fibre volley or by a change in paired-pulse potentiation, consistent with a postsynaptic locus of CCh action. 3. Intracellular recordings from voltage-clamped neurons of inward current evoked by iontophoretically applied alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl-D-aspartate (NMDA) revealed that, while cellular responses to NMDA rose transiently upon superfusion with 0.5 microM CCh, responses to AMPA increased gradually and remained potentiated after washout of CCh. 4. LTP(m) is mediated by an M2 muscarinic receptor. Two M2 muscarinic receptor antagonists, methoctramine and AFDX-116, blocked LTP(m). The M2 agonist oxotremorine induced LTP(m) at low agonist concentrations. None of the M1 and M3 receptor agonists and antagonists tested affected LTP(m). 5. Muscarinic fast onset depression of the EPSP was seen in response to higher concentrations of CCh (2-5 mu M). This depression was accompanied by an increase in paired-pulse potentiation, indicating a possible presynaptic locus of action. The M3 muscarinic receptor antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) blocked the muscarinic depression of the EPSP slope. M1, M2 and M4 muscarinic antagonists did not block this response. 6. Blockade of the muscarinic depression by 4-DAMP did not uncover a suppressed LTP(m). However, addition of picrotoxin facilitated the expression of LTP(m) induced by high concentrations of CCh, indicating an involvement of interneurons in regulation of LTP(m). 7. Cholinergic denervation produced by fimbria-fornix transection resulted in supersensitivity of both M2- and M3-mediated effects, indicating that the receptors mediating these effects are not located on presynaptic cholinergic fibres. In the presence of 4-DAMP and picrotoxin the dose-response curve for CCh-induced effects in slices from lesioned animals was shifted to the left relative to that of normal animals, indicating a supersensitivity of both receptor types.
