Nicotine-induced norepinephrine release in hypothalamic paraventricular nucleus and amygdala is mediated by N-methyl-D-aspartate receptors and nitric oxide in the nucleus tractus solitarius

Rongjie Zhao, Hao Chen, Burt Sharp

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36 Citations (Scopus)

Abstract

The noradrenergic projections from brainstem nucleus tractus solitarius (NTS) to hypothalamic paraventricular nucleus (PVN) and amygdala (AMYG) are involved in nicotine-related stress responses and drug craving. Previous studies demonstrated that i.v. nicotine-induced norepinephrine (NE) release in the PVN and AMYG depends on nicotinic cholinergic receptors in the brainstem. However, the direct site and mechanism of nicotine's action in brainstem are unknown. The present study determined the roles of NTS ionotropic glutamate receptors and nitric oxide (NO) in the effects of both local and systemic nicotine on NE release in PVN and AMYG. In male rats, an intra-NTS microinjection of nicotine (1.2 μg free base) or i.v. nicotine infusion (0.065 or 0.09 mg/kg) significantly increased NE levels in PVN and AMYG microdialysates. Prior microinjection of the N-methyl-D-aspartate (NMDA) receptor antagonist, DL-2-amino-5-phosphonopentanoic acid (0.75 or 1.5 μg), but not an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonist, dose dependently nearly abolished both PVN and AMYG NE responses to nicotine administered into NTS or systemically. NO involvement was assessed with intra-NTS microinjections of the nonselective nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester hydrochloride (10-30 nmol), or the NO scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (0.1- 0.2 nmol); both agents dose dependently inhibited i.v. nicotine-induced NE release. These results indicate that nicotine-induced NE release in PVN and AMYG is mediated entirely through the local effects of nicotine on NTS glutamate afferents and NMDA receptors that, in part, stimulate NO production, resulting in activation of noradrenergic neurons. Therefore, nicotine acts indirectly on noradrenergic NTS neurons to elicit NE release in forebrain structures.

Original languageEnglish (US)
Pages (from-to)837-844
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume320
Issue number2
DOIs
StatePublished - Feb 1 2007

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Solitary Nucleus
Amygdala
N-Methyl-D-Aspartate Receptors
Nicotine
Norepinephrine
Nitric Oxide
Paraventricular Hypothalamic Nucleus
Microinjections
Brain Stem
2-Amino-5-phosphonovalerate
Isoxazoles
Ionotropic Glutamate Receptors
Adrenergic Neurons
NG-Nitroarginine Methyl Ester
Nicotinic Receptors
Cholinergic Receptors
Prosencephalon
Nitric Oxide Synthase
Glutamic Acid

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

@article{0177be9ad4914419a3f9967a37607c54,
title = "Nicotine-induced norepinephrine release in hypothalamic paraventricular nucleus and amygdala is mediated by N-methyl-D-aspartate receptors and nitric oxide in the nucleus tractus solitarius",
abstract = "The noradrenergic projections from brainstem nucleus tractus solitarius (NTS) to hypothalamic paraventricular nucleus (PVN) and amygdala (AMYG) are involved in nicotine-related stress responses and drug craving. Previous studies demonstrated that i.v. nicotine-induced norepinephrine (NE) release in the PVN and AMYG depends on nicotinic cholinergic receptors in the brainstem. However, the direct site and mechanism of nicotine's action in brainstem are unknown. The present study determined the roles of NTS ionotropic glutamate receptors and nitric oxide (NO) in the effects of both local and systemic nicotine on NE release in PVN and AMYG. In male rats, an intra-NTS microinjection of nicotine (1.2 μg free base) or i.v. nicotine infusion (0.065 or 0.09 mg/kg) significantly increased NE levels in PVN and AMYG microdialysates. Prior microinjection of the N-methyl-D-aspartate (NMDA) receptor antagonist, DL-2-amino-5-phosphonopentanoic acid (0.75 or 1.5 μg), but not an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonist, dose dependently nearly abolished both PVN and AMYG NE responses to nicotine administered into NTS or systemically. NO involvement was assessed with intra-NTS microinjections of the nonselective nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester hydrochloride (10-30 nmol), or the NO scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (0.1- 0.2 nmol); both agents dose dependently inhibited i.v. nicotine-induced NE release. These results indicate that nicotine-induced NE release in PVN and AMYG is mediated entirely through the local effects of nicotine on NTS glutamate afferents and NMDA receptors that, in part, stimulate NO production, resulting in activation of noradrenergic neurons. Therefore, nicotine acts indirectly on noradrenergic NTS neurons to elicit NE release in forebrain structures.",
author = "Rongjie Zhao and Hao Chen and Burt Sharp",
year = "2007",
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T1 - Nicotine-induced norepinephrine release in hypothalamic paraventricular nucleus and amygdala is mediated by N-methyl-D-aspartate receptors and nitric oxide in the nucleus tractus solitarius

AU - Zhao, Rongjie

AU - Chen, Hao

AU - Sharp, Burt

PY - 2007/2/1

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N2 - The noradrenergic projections from brainstem nucleus tractus solitarius (NTS) to hypothalamic paraventricular nucleus (PVN) and amygdala (AMYG) are involved in nicotine-related stress responses and drug craving. Previous studies demonstrated that i.v. nicotine-induced norepinephrine (NE) release in the PVN and AMYG depends on nicotinic cholinergic receptors in the brainstem. However, the direct site and mechanism of nicotine's action in brainstem are unknown. The present study determined the roles of NTS ionotropic glutamate receptors and nitric oxide (NO) in the effects of both local and systemic nicotine on NE release in PVN and AMYG. In male rats, an intra-NTS microinjection of nicotine (1.2 μg free base) or i.v. nicotine infusion (0.065 or 0.09 mg/kg) significantly increased NE levels in PVN and AMYG microdialysates. Prior microinjection of the N-methyl-D-aspartate (NMDA) receptor antagonist, DL-2-amino-5-phosphonopentanoic acid (0.75 or 1.5 μg), but not an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonist, dose dependently nearly abolished both PVN and AMYG NE responses to nicotine administered into NTS or systemically. NO involvement was assessed with intra-NTS microinjections of the nonselective nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester hydrochloride (10-30 nmol), or the NO scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (0.1- 0.2 nmol); both agents dose dependently inhibited i.v. nicotine-induced NE release. These results indicate that nicotine-induced NE release in PVN and AMYG is mediated entirely through the local effects of nicotine on NTS glutamate afferents and NMDA receptors that, in part, stimulate NO production, resulting in activation of noradrenergic neurons. Therefore, nicotine acts indirectly on noradrenergic NTS neurons to elicit NE release in forebrain structures.

AB - The noradrenergic projections from brainstem nucleus tractus solitarius (NTS) to hypothalamic paraventricular nucleus (PVN) and amygdala (AMYG) are involved in nicotine-related stress responses and drug craving. Previous studies demonstrated that i.v. nicotine-induced norepinephrine (NE) release in the PVN and AMYG depends on nicotinic cholinergic receptors in the brainstem. However, the direct site and mechanism of nicotine's action in brainstem are unknown. The present study determined the roles of NTS ionotropic glutamate receptors and nitric oxide (NO) in the effects of both local and systemic nicotine on NE release in PVN and AMYG. In male rats, an intra-NTS microinjection of nicotine (1.2 μg free base) or i.v. nicotine infusion (0.065 or 0.09 mg/kg) significantly increased NE levels in PVN and AMYG microdialysates. Prior microinjection of the N-methyl-D-aspartate (NMDA) receptor antagonist, DL-2-amino-5-phosphonopentanoic acid (0.75 or 1.5 μg), but not an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonist, dose dependently nearly abolished both PVN and AMYG NE responses to nicotine administered into NTS or systemically. NO involvement was assessed with intra-NTS microinjections of the nonselective nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester hydrochloride (10-30 nmol), or the NO scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (0.1- 0.2 nmol); both agents dose dependently inhibited i.v. nicotine-induced NE release. These results indicate that nicotine-induced NE release in PVN and AMYG is mediated entirely through the local effects of nicotine on NTS glutamate afferents and NMDA receptors that, in part, stimulate NO production, resulting in activation of noradrenergic neurons. Therefore, nicotine acts indirectly on noradrenergic NTS neurons to elicit NE release in forebrain structures.

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