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Adrenocorticotropin Response and Nicotine-Induced Norepinephrine Secretion in the Rat Paraventricular Nucleus Are Mediated through Brainstem Receptors¹

Endocrine-Neuroscience Laboratories (Y.F., S.G.M., J.D.V., B.M.S.), Minneapolis Medical Research Foundation; and the Departments of Medicine (S.G.M., B.M.S.), Hennepin County Medical Center and the University of Minnesota, Minneapolis, Minnesota 55404

Address all correspondence and requests for reprints to: Burt M. Sharp, M.D., Endocrine-Neuroscience Laboratories, Minneapolis Medical Research Foundation, 914 South Eighth Street, Minneapolis, Minnesota 55404. E-mail: sharp002{at}maroon.tc.umn.edu

Nicotine is a potent stimulus for the secretion of ACTH, and norepinephrinergic neurons originating in the brainstem are involved. Prior reports using in vivo microdialysis in alert rats have shown that nicotine, administered ip or into the fourth ventricle, stimulated the release of norepinephrine (NE) into the hypothalamic paraventricular nucleus (PVN), the site of neurons containing CRH. In the present studies, rats received an iv infusion of nicotine into the jugular vein on alternate days during their active (dark) phase; therefore, direct correlations between the levels of NE microdialyzed from the PVN and plasma ACTH could be made in each animal. Nicotine administered iv (0.045–0.135 mg/kg) elicited dose-dependent increases in both NE and ACTH (P < 0.01). A significant correlation was found between nicotine-stimulated NE release in the PVN and ACTH secretion (r = 0.91, P < 0.01). To address whether the site(s) of action of nicotine was on presynaptic receptors on NE terminals in the PVN or on receptors on neurons in brainstem regions accessible from the fourth ventricle, the nicotinic cholinergic antagonist, mecamylamine (0.1–4.8 µg), was microinjected directly into the PVN or into the fourth ventricle before nicotine infusion. Fourth-ventricular administration of mecamylamine (1.6 µg) or higher, before iv nicotine (0.09 mg/kg), completely blocked both NE release in the PVN (IC₅₀ = 0.64 µg) and ACTH secretion (IC₅₀ = 0.40 µg) (P < 0.01, compared with vehicle before nicotine), whereas it was ineffective when injected directly into the PVN. The results demonstrate that the nicotinic cholinergic receptors in the brainstem, rather than presynaptic receptors within the PVN itself, mediate nicotine-stimulated PVN NE release and ACTH secretion.

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