Desensitization of muscarinic stimulated hippocampal cell firing is related to phosphoinositide hydrolysis and inhibited by lithium.

The potency and efficacy of a series of muscarinic agonists for stimulation of neuronal firing rate was compared with stimulation of phosphoinositide (PPI) hydrolysis in similar hippocampal slice preparations. Carbachol, muscarine, pilocarpine, arecoline, bethanechol and oxotremorine varied in potency, but stimulated neuronal firing to a similar extent. At higher concentrations, all of the drugs except oxotremorine caused a decrease in firing rate (desensitization). A comparison of the concentration-response curves for PPI hydrolysis and neuronal firing rates showed that desensitization occurred at a threshold level of PPI hydrolysis. Although the concentration of drug that caused the decrease in firing rate was different for each agonist, the level of PPI hydrolysis at the desensitizing concentration was similar, with the exception of oxotremorine. Oxotremorine, the weakest agonist for stimulation of PPI hydrolysis, did not reach this PPI hydrolysis threshold and did not exhibit desensitization. Oxotremorine was also capable of both blocking and reversing the desensitization caused by carbachol. Low concentrations of pirenzepine, an M1 selective muscarinic antagonist, reversed carbachol desensitization. Concentrations of lithium that disrupt the phosphoinositide cycle by preventing recycling of free inositol (Allison, J. H., et al.: Biochem. Biophys. Res. Commun. 71: 664-670, 1976; Hallcher, L. M. and Sherman, W. R.: J. Biol. Chem. 225: 10896-10901, 1980) slowly reversed desensitization. Furthermore, inositol added to the buffer could re-establish desensitization in lithium-treated preparations. These studies suggest that muscarinic desensitization of hippocampal cell firing is related to large increases in phosphoinositide hydrolysis. Muscarinic receptor-stimulated increases in cell firing may be mediated by a subtype or state of muscarinic receptor different from that mediating phosphoinositide hydrolysis and desensitization.