NICOTINE-INDUCED NOREPINEPHRINE RELEASE IN THE RAT AMYGDALA AND HIPPOCAMPUS IS MEDIATED THROUGH BRAIN-STEM NICOTINIC CHOLINERGIC RECEPTORS

Previous studies have shown that nicotine stimulates norepinephrine (N E) release in the rat hypothalamic paraventricular nucleus, which in t urn activates the hypothalamo-pituitary-adrenal axis. In the present s tudy, nicotine induced NE release in the amygdala (AMYG) and the hippo campus (HP) of the same rat in vivo. Nicotine (0.065-0.135 mg/kg i.v. at a rate of 0.09 mg/kg/60 sec) dose-dependently increased NE release at both sites with similar potencies. To determine whether the site of action of nicotine is in the brainstem, which contains the noradrener gic cell bodies projecting to AMYG and HP, nicotinic cholinergic recep tor (NAchR) antagonists were injected into the cerebral aqueduct befor e i.v. nicotine. Use of the following antagonists enabled partial char acterization of the NAchRs mediating NE secretion: mecamylamine (Mec), dihydro-beta-erythroidine (DH beta E), methyllycaconitine (MLA) and a lpha-bungarotoxin (alpha-BTX). Mec inhibited 80% of NE release in AMYG and 87% in HP (IC50 = 6 nmol for both regions). DH beta E blocked 62% of NE release in AMYG (IC50 = 8 nmol) and 63% in HP (IC50 = 15 nmol). Similar to DH beta E, MLA inhibited 60% of NE release in AMYG and 66% in HP (IC50 = 5 nmol for both regions). In contrast, alpha-BTX had no effect on NE release in either region. These results indicate that br ainstem NAchRs accessible from the fourth ventricle mediate nicotine-s timulated NE secretion in AMYG and HP. Taken together with prior inves tigations showing the brainstem expression of mRNAs encoding NAchR sub types and the selectivity of antagonists for NAchR subtypes, the prese nt studies suggest that brainstem alpha-3 subunits may be involved.