ROLE OF PROSTANOIDS IN THE REGULATION OF CENTRAL CHOLINERGIC RECEPTORSENSITIVITY

Tachyphylaxis develops to the hypertensive response to central (i.c.v. ) injection of carbachol in conscious rats. This pressor response exhi bits tachyphylaxis if the injection is repeated within 8 hr of the fir st injection. Blockade of brain prostaglandin synthesis with indometha cin does not inhibit the pressor response to carbachol in naive rats, but eliminates the pressor response to carbachol when the muscarinic a gonist is repeated within a few hours of the first injection. If the t ime interval is extended to permit return of the full response (i.e., 24 hr later), indomethacin no longer inhibits the pressor response. Th e related cyclooygenase inhibitor meclofenamate produced effects which were identical to those of indomethacin, but at approximately 10-fold higher doses. When shorter acting drugs (duration of action < 30 min) , physostigmine or arecoline, were used according to the same paradigm , indomethacin was less effective at inhibiting the pressor response t o the second injection, even when the two agonist injections were spac ed only 30 min apart. The ability of indomethacin to enhance central m uscarinic receptor tachyphylaxis was also observed in carbachol-induce d hypothermia. The density of diencephalic muscarinic receptors was es timated by using N-[H-3]methylscopolamine as a probe. Carbachol-induce d a down-regulation of muscarinic receptors, and indomethacin increase d the extent of this down regulation. These findings suggest that pros taglandins play a role in the development of tachyphylaxis to brain mu scarinic receptor stimulation: activation of prostaglandin synthesis m ay decelerate the development of desensitization to muscarinic agonist s.