Abstract
Previous studies have shown that nicotine stimulates norepinephrine (NE) release in the rat hypothalamic paraventricular nucleus, which in turn activates the hypothalamo-pituitary-adrenal axis. In the present study, nicotine induced NE release in the amygdala (AMYG) and the hippocampus (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 noradrenergic cell bodies projecting to AMYG and HP, nicotinic cholinergic receptor (NAchR) antagonists were injected into the cerebral aqueduct before i.v. nicotine. Use of the following antagonists enabled partial characterization of the NAchRs mediating NE secretion: mecamylamine (Mec), dihydro-β-erythroidine (DHβE), methyllycaconitine (MLA) and α-bungarotoxin (α-BTX). Mec inhibited 80% of NE release in AMYG and 87% in HP (IC50 = 6 nmol for both regions). DHβE blocked 62% of NE release in AMYG (IC50 = 8 nmol) and 63% in HP (IC50 = 15 nmol). Similar to DHβE, MLA inhibited 60% of NE release in AMYG and 66% in HP (IC50 = 5 nmol for both regions). In contrast, α-BTX had no effect on NE release in either region. These results indicate that brainstem NAchRs accessible from the fourth ventricle mediate nicotine-stimulated NE secretion in AMYG and HP. Taken together with prior investigations showing the brainstem expression of mRNAs encoding NAchR subtypes and the selectivity of antagonists for NAchR subtypes, the present studies suggest that brainstemalpha-3 subunits may be involved.
Footnotes
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Send reprint requests to: Burt M. Sharp, M.D., Institute for Brain and Immune Disorders, Minneapolis Medical Research Foundation, 914 South Eighth Street, Minneapolis, MN 55404.
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↵1 This work was supported by NIH grant DA03977 (to B.M.S.).
- Abbreviations:
- AMYG
- amygdala
- α-BTX
- α-bungarotoxin
- DHβE
- dihydro-β-erythroidine
- HP
- hippocampus
- HPA
- hypothalamo-pituitary-adrenal
- HPLC
- high-performance liquid chromatography
- KRB
- Kreb’s Ringer Buffer
- LC
- locus coeruleus
- Mec
- mecamylamine
- MLA
- methyllycaconitine
- NAchRs
- nicotinic cholinergic receptors
- NE
- norepinephrine
- NTS
- nucleus tractus solitarius
- PVN
- hypothalamic paraventricular nucleus
- CNS
- central nervous system
- CSF
- cerebrospinal fluid
- EDTA
- ethylenediaminetetraacetic acid
- Received August 5, 1997.
- Accepted November 24, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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