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 g 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 g), but not an ␣-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.

Chronic Nicotine Self-Administration Augments Hypothalamic–Pituitary–Adrenal Responses to Mild Acute Stress

“…We further demonstrated that nicotine indirectly induces ACTH secretion from the anterior pituitary by directly activating noradrenergic areas of the nucleus tractus solitarius (Matta et al, 1998;Zhao et al, 2007).…”

“…Corticotropin-releasing factor (CRF) neurons in the hypothalamic paraventricular nucleus (PVN), which are pivotal regulators of ACTH secretion, are not directly activated by nicotine (Matta et al, 1987). Instead, nicotine indirectly activates PVN CRF neurons (Matta et al, 1990) by stimulating a cascade of neurotransmitters in the nucleus tractus solitarius (NTS) that activate noradrenergic projections to the PVN (Zhao et al, 2007).…”

Nicotine Self-Administration Differentially Regulates Hypothalamic Corticotropin-Releasing Factor and Arginine Vasopressin mRNAs and Facilitates Stress-Induced Neuronal Activation

“…In animals, acute injection of nicotine, the principal psychoactive component of tobacco smoke, is a potent stimulus for secretion of the stress-responsive hypothalamo-pituitary-adrenal (HPA) axis hormones ACTH (Conte-Devolx et al, 1981;Cam and Bassett, 1983;Matta et al, 1987) and corticosterone (Balfour et al, 1975;Cam and Bassett, 1983). Acutely injected nicotine increased glutamate release and enhanced NMDA receptor activity in noradrenergic regions of the nucleus tractus solitarius projecting to the hypothalamic paraventricular nucleus (PVN) (Zhao et al, 2007), projections shown to stimulate norepinephrine release and activate corticotropin-releasing factor (CRF) neurons in PVN (Valentine et al, 1996;Matta et al, 1998). However, the effect of chronically self-administered nicotine on these stress-responsive systems has not been fully resolved.…”

Intra-accumbal and Peripheral administration of nicotine reduces the side-effects of Inescapable Stress

“…It has been reported that the reduced level of dopamine in the nucleus accumbens recovers the animal's ability to acquire used to stress following inescapable stress (Dubrovsky, 2005;Viveros et al, 2007;Colomer and Olivos-Oré et al, 2010;Hunter and Bloss et al, 2010). Various parts of reward system are involved in the variation of stress responses and the nucleus accumbens as a main parts of this reward system, acting a vital role in inhibiting the effects of stress (Zhao et al, 2007). In the present study, the stimulation of nicotinic receptors in the nucleus accumbens induced different responses indicating the influence of the cholinergic system in the nucleus accumbens.…”