Stressors affect the use of a wide range of substances involved in drug abuse; for example, stressful environments have been reported to stimulate cigarette smoking. Stressors may affect drug self-administration (SA) through their diverse effects on stress-responsive CNS systems, such as those regulating neurohormonal and noradrenergic function within the hypothalamus (e.g. paraventricular nucleus; PVN) and brainstem, respectively. We hypothesize that chronic nicotine SA, acting as a stressor, activates and modifies these stress-responsive systems, leading to changes in their stress-responsiveness.
The specific aims of this application are focused on characterizing and elucidating mechanisms underlying these changes in HPA and PVN stress-responsivity induced by chronic nicotine SA. A unique model of daily (23 h/d) unlimited access to nicotine SA will be used to study the effects of nicotine on HPA and PVN responses to stressors. Spec.
Aim 1 will characterize the effects of chronic nicotine SA on hypothalamo-pituitary-adrenal (HPA) activation (plasma ACTH/corticosterone) and PVN norepinephrine release by a range of stressors at different intensities. In Spec.
Aim 2, mechanisms responsible for the altered stress-responsiveness of chronic nicotine SA rats will be determined. These will include studies on the effects of chronic nicotine SA on PVN neuropeptide mRNA expression, the activation of PVN c-fos expression by stressors, and the role of PVN noradrenergic inputs in the PVN and HPA responses to stressors. Complementary studies will also identify nicotinic cholinergic receptors that mediate activation of the brainstem-PVN noradrenergic axis by nicotine. Spec.
Aim 3 will characterize the role of glutamate and NTS NMDA receptors in (1) nicotine-induced PVN NE secretion and HPA activation and in (2) the reduction of stress-induced PVN NE release caused by chronic nicotine SA. Preliminary observations indicate that specific NMDA receptor subunits in the nucleus tractus solitarius (NTS), with noradrenergic projections to the PVN, are downregulated by nicotine SA and that brainstem glutamate is necessary for the PVN NE response to nicotine. Therefore, studies in this section will involve the quantitation of specific NTS NMDA receptor subunits by immunoblotting. The functional effects of NMDA receptor downregulation also will be characterized by measuring PVN NE responses and the induction of NTS cfos expression by NMDA during nicotine SA. We postulate that NTS glutamate may be involved in stress-induced PVN NE secretion. Therefore, studies will evaluate whether inhibition of NTS NMDA receptors attenuates the PVN NE response to an acute stressor. Together, the studies in this proposal will clarify the effects of chronic nicotine SA on HPA responsiveness to stressors and on underlying adaptive changes in the brainstem HPA axis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA003977-21A2
Application #
6863589
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Hoffman, Allison
Project Start
1985-03-31
Project End
2009-12-31
Budget Start
2005-04-01
Budget End
2005-12-31
Support Year
21
Fiscal Year
2005
Total Cost
$410,670
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Yu, Guoliang; Chen, Hao; Sharp, Burt M (2014) Amplified reacquisition of nicotine self-administration in rats by repeated stress during abstinence. Psychopharmacology (Berl) 231:3189-95
Yu, Guoliang; Sharp, Burt M (2012) Nicotine modulates multiple regions in the limbic stress network regulating activation of hypophysiotrophic neurons in hypothalamic paraventricular nucleus. J Neurochem 122:628-40
Yu, Guoliang; Chen, Hao; Wu, Xingjun et al. (2010) Nicotine self-administration differentially modulates glutamate and GABA transmission in hypothalamic paraventricular nucleus to enhance the hypothalamic-pituitary-adrenal response to stress. J Neurochem 113:919-29
Yu, Guoliang; Sharp, Burt M (2010) Nicotine self-administration diminishes stress-induced norepinephrine secretion but augments adrenergic-responsiveness in the hypothalamic paraventricular nucleus and enhances adrenocorticotropic hormone and corticosterone release. J Neurochem 112:1327-37
Chen, Hao; Fu, Yitong; Sharp, Burt M (2008) Chronic nicotine self-administration augments hypothalamic-pituitary-adrenal responses to mild acute stress. Neuropsychopharmacology 33:721-30
Wang, Fan; Chen, Hao; Sharp, Burt M (2008) Neuroadaptive changes in the mesocortical glutamatergic system during chronic nicotine self-administration and after extinction in rats. J Neurochem 106:943-56
Yu, Guoliang; Chen, Hao; Zhao, Wenyuan et al. (2008) Nicotine self-administration differentially regulates hypothalamic corticotropin-releasing factor and arginine vasopressin mRNAs and facilitates stress-induced neuronal activation. J Neurosci 28:2773-82
Chen, Hao; Matta, Shannon G; Sharp, Burt M (2007) Acquisition of nicotine self-administration in adolescent rats given prolonged access to the drug. Neuropsychopharmacology 32:700-9
Zhao, Rongjie; Chen, Hao; Sharp, Burt M (2007) 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. J Pharmacol Exp Ther 320:837-44
Wang, Fan; Chen, Hao; Steketee, Jeffery D et al. (2007) Upregulation of ionotropic glutamate receptor subunits within specific mesocorticolimbic regions during chronic nicotine self-administration. Neuropsychopharmacology 32:103-9

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