Cigarette smoking has been recognized as the most important source of preventable morbidity and premature mortality in the United States. Amongst the potential psychoactive agents in tobacco smoke, nicotine appears to be the one primarily responsible for maintaining and regulating tobacco use. Stressful environments appear to present cues that enhance smoking, and chronic smokers report that smoking may have stress-reducing effects. Experimentally, the effects of nicotine and smoking on CNS responses to stress in animals and humans are inconsistent. These differences suggest that the dose, duration, schedule of administration and nature of the stressor are important determinants of the interaction between nicotine and CNS responses to stress. The proposed studies will elucidate the effects of chronic self-administered nicotine on the stress-responsive systems of the CNS, both neurohormonal (i.e., HPA axis) and neurotransmitter [i.e., CRH and noradrenergic systems (NE)]. These studies will determine how the responsiveness of these systems to stressors is modified by unlimited access to self-administered nicotine, focusing on the following three regions of the brain that are involved in important aspects of the stress response: hippocampus (HP), amygdala, and paraventricular nucleus of the hypothalamus (PVN). Using (I) in vivo microdialysis to measure local NE secretion, (ii) in situ hybridization to measure heteronuclear CRH RNA as an index of acute neuronal activity (and CRH mRNA for cumulative changes), and (iii) tyrosine hydroxylase (TOM) mRNA and protein to detect cumulative changes in the function of NE neurons, specific aim 1 will characterize the effects of chronic nicotine on CNS noradrenergic projections and CRH systems within the PVN, amygdala and HP; the HPA axis will be assessed further by measuring plasma ACTH and corticosterone. Nicotine-induced differences in NE secretion within these three regions will be linked to functional changes in the noradrenergic brainstem regions that give rise to these NE projections.
Specific aim 2 will determine how stress-induced HPA activity and NE secretion is affected by nicotine self-administration. Experiments will characterize ACTH/corticosterone secretion and CRH neuronal responses in the PVN and amygdala to a battery of acute stressors; parallel studies will assess stress-induced NE release in the PVN, amygdala and HP.
Specific aim 3 will identify mechanisms whereby nicotinic cholinergic receptors (NAchRs) in the HP and amygdala, in coordination with those in the brainstem, mediate the release of NE in the HP and amygdala. Experiments will clarify the role of alpha-bungarotoxin- sensitive NAchRs in these regions. In summary, these studies will provide a mechanistic understanding of how chronic exposure to nicotine affects pivotal neurohumoral and neurochemical mediators of the CNS response to stress.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Human Development Research Subcommittee (NIDA)
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Hoffman, Allison
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University of Tennessee Health Science Center
Schools of Medicine
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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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