Facilitation of cholinergic transmission by substance P methyl ester in the mouse hippocampal slice preparation

Using sharp microelectrode recording from CA1 pyramidal neurons of the adul t mouse hippocampal slice preparation, we studied the modulatory action of the selective neurokinin 1 (NK1) receptor agonist substance P methyl ester (SPME), a peptidase-resistant analogue of the peptide substance P (SP), on cholinergic responses. While SPME (0.1-1 mu m) had only slight effects on m embrane potential and input resistance of CA1 neurons, it largely and rever sibly enhanced the membrane depolarization and oscillatory activity induced by the cholinergic agonist carbachol (CCh; 0.1-100 mu m). This effect of S PME was prevented by the selective NK1 receptor antagonist SR 140333 (4 mu m). In about half of the tested neurons the action of SPME was preserved in tetrodotoxin (TTX) solution, suggesting that it partly occurred at the lev el of pyramidal cells. Cholinergic slow excitatory postsynaptic potentials (sEPSPs) were reversibly enhanced by SPME which increased their amplitude a nd prolonged any associated bursting activity. This action was also blocked by SR 140333. The present results suggest that SPME largely enhances choli nergic activity in the mouse hippocampus, an effect which can help to expla in, in this brain area, the recently reported facilitation of seizures by S P.