Nicotine self-administration diminishes stress-induced norepinephrine secretion but augments adrenergic-responsiveness in the hypothalamic paraventricular nucleus and enhances adrenocorticotropic hormone and corticosterone release


Address correspondence and reprint requests to Burt M. Sharp, Suite 115 Crowe building, 874 Union Ave., Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163, USA. E-mail:


J. Neurochem. (2010) 112, 1327–1337.


Chronic nicotine self-administration augments the thalamo-pituitary-adrenal (HPA) responses to stress. Altered neuropeptide expression within corticotropin-releasing factor (CRF) neurons in the hypothalamic paraventricular nucleus (PVN) contributes to this enhanced HPA response to stress. Herein, we determined the role of norepinephrine, a primary regulator of CRF neurons, in the responses to footshock during nicotine self-administration. On day 12–15 of self-administration, microdialysis showed nicotine reduced PVN norepinephrine release by footshock (< 50% of saline). Yet, the reduction in footshock-induced adrenocorticotropic hormone and corticosterone secretion because of intra-PVN prazosin (α1 adrenergic antagonist) was significantly greater in rats self-administering nicotine (2-fold) than saline. Additionally, PVN phenylephrine (α1 agonist) stimulated adrenocorticotropic hormone and corticosterone release to a similar extent in unstressed rats self-administering nicotine or saline. Nicotine self-administration also decreased footshock-induced c-Fos expression in the nucleus of the solitary tract-A2/C2 catecholaminergic neurons that project to the PVN. Therefore, footshock-induced nucleus of the solitary tract activation and PVN norepinephrine input are both attenuated by nicotine self-administration, yet PVN CRF neurons are more responsive to α1 stimulation, but only during stress. This plasticity in noradrenergic regulation of PVN CRF neurons provides a new mechanism contributing to the HPA sensitization to stress by nicotine self-administration and smoking.