EFFECTS OF SEROTONERGIC AGENTS ON NEURONAL NICOTINIC ACETYLCHOLINE-RECEPTORS

In Xenopus oocytes expressing neuronal nicotinic acetylcholine recepto rs (nAcChoRs), made up of alpha 2 and beta 4 subunits, acetylcholine ( AcCho) elicited ionic membrane currents (AcCho currents) that were mod ulated by serotonergic agents. Both agonists and antagonists specific for various serotonin (5-hydroxytryptamine, 5HT) receptor subtypes int eracted directly with alpha 2 beta 4 nAcChoRs: 5HT, (+/-)-8-hydroxy-2- (di-n-propylamino) tetralin, methysergide, spiperone, and ketanserin r eversibly reduced the amplitude of AcCho currents and accelerated thei r decay. The AcCho-current time course decayed with two exponential fu nctions. In the presence of 5HT, the fast time constant of current dec ay (tau(f)) was not greatly modified, but the slow time constant (tau( s)) was reduced. With AcCho and 5HT both at 100 mu M, tau(s) was reduc ed from 140 s to 85 s. The order of potency for inhibition of AcCho cu rrent amplitudes was (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin > me thysergide > spiperone > ketanserin > 5HT. The inhibition was voltage- dependent but the magnitude of the voltage dependence for the differen t blockers did not correspond to their blocking potency: e.g., the blo ck with spiperone was stronger than with 5HT, but it was less voltage- dependent. Our results suggest that serotonergic agents block neuronal nAcChoRs in a noncompetitive manner, similar to the block of muscle n AcChoR by curare and other substances. These results show that neurona l nAcChoR channels that have been activated by their specific neurotra nsmitter may be modulated by nonspecific neurotransmitters and their a ntagonists. These effects may help to better understand brain function s as well as the mode of action of the many serotonergic agents that a re used in medical practice.