Action of nicotine on the ascending reticular activating system

Abstract

Synchronization of the electroencephalogram was produced by midpontine brainstem transection in the rabbit, cat and dog, and by high pontine transection in the monkey. After transection, i.v. injections of 10-20 [mu]g/kg of nicotine produced EEG activation responses in all four species. The mechanism and site of action of the EEG activation effect of nicotine was explored in the dog. It has been shown that peripheral nerve receptors are not essentially involved in nicotine induced EEG activation. Furthermore, the EEG activation effect of nicotine does not appear related to fluctuations in blood pressure, or to increases in circulating levels of epinephrine, norepinephrine, 5-hydroxytryptamine, or vasopressin. Studies in reserpine-pretreated dogs suggest nicotine does not owe its EEG activation effect to the release of central stores of catechol amines of 5-hydroxytryptamine. No evidence was obtained, however, which denies the possibility that nicotine produced EEG activation by a cholinergic mechanism. It is tentatively concluded that a likely mechanism by which nicotine produces EEG activation is by mimicking, or possibly releasing, acetylcholine in the central nervous system. Because nicotine did not produce EEG activation in prepontine or postmammillary dogs, but altered electrical activity of the dog reticular slab, a ponto-mesencephalic site of action for the EEG activation effect of nicotine is proposed.Although nicotine induced EEG activation does not appear to be mediated by an increase in circulating levels of vasopressin, attention is drawn to the possibility that the release of vasopressin may be involved in the central nervous system pharmacology of nicotine, perhaps in regard to the development of acute tolerance to certain central actions of nicotine.It is noted that in all four species studied, the 10-20 [mu]g/kg EEG activation dose of nicotine corresponds to blood levels of nicotine which are commonly achieved in the habitual use of tobacco by man. Study of the central effects of nicotine analogs, particularly non-quarternary analogs, is suggested.