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.
Footnotes
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This work was supported by the National Institute on Drug Abuse (Grant DA-03977 to B.M.S.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.112474.
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ABBREVIATIONS: PVN, hypothalamic paraventricular nucleus; AMYG, amygdala; nAChR, nicotinic cholinergic receptor; NE, norepinephrine; NTS, nucleus tractus solitarius; pcPVN, parvocellular PVN; ACTH, adrenocorticotropin; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; NMDA, N-methyl-d-aspartate; nNOS, neuronal nitric oxide synthase; NO, nitric oxide; AP-5, dl-2-amino-5-phosphonopentanoic acid; CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione; NOS, nitric-oxide synthase; l-NAME, NG-nitro-l-arginine methyl ester hydrochloride; carboxy-PTIO, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; KRB, Krebs-Ringer buffer; LC, locus coeruleus; ANOVA, analysis of variance; Nic, nicotine.
- Received August 14, 2006.
- Accepted November 7, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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