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

Abstract

J. Neurochem. (2010) 112, 1327–1337. Abstract 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.

Chronic Psychosocial Stress Exacerbates Impairment of Synaptic Plasticity in &#946;-Amyloid Rat Model of Alzheimers Disease: Prevention by Nicotine

“…However, nicotine was previously reported to acutely elevate corticosterone secretion, an effect that desensitizes after repeated injections or long-term self-administration of the drug [96,97]. Furthermore, chronic nicotine self-administration was shown to augment corticosterone responses to novel stressors such as foot shock stress [96,98]. Therefore, it seems unlikely that nicotine can reduce corticosterone levels in our A animals.…”

Substance abuse, memory, and post-traumatic stress disorder

“…Although higher doses of nicotine can act as chronic stressors (Yu & Sharp, 2010), the doses reviewed here, which match the levels reported in human smokers (Davis et al, 2005), selectively alter learning via the modulation of hippocampal and medial prefrontal signaling, rather than by affecting general stress levels. Additionally, this work demonstrates that fear conditioning is sensitive to the different patterns of nicotine exposure that are observed in human smokers and patients diagnosed with PTSD.…”

“…Importantly, at the these doses, nicotine does not affect delay fear conditioning, regardless of conditioning strength (Gould & Higgins, 2003), suggesting that nicotine enhances contextual and trace conditioning via the enhancement of learning, rather than altering anxiety or stress. However, it should be noted that higher doses of nicotine are anxiogenic and can act as stressors (Yu & Sharp, 2010). Interestingly, nicotine can also enhance cued extinction after delay fear conditioning (Elias, Gulick, Wilkinson, & Gould, 2010), a task that relies on cortical substrates similar to those that support the acquisition of trace fear conditioning (Stafford, Raybuck, Ryabinin, & Lattal, 2012).…”

Hindbrain noradrenergic A2 neurons: diverse roles in autonomic, endocrine, cognitive, and behavioral functions

“…Interestingly, conditioned preference for morphine is absent in DbH knock-out mice in which NE synthesis is interrupted, but preference is restored if DbH is rescued to restore NA signaling within and from the NTS, but not the LC (176). Repeated nicotine self-administration increases NA receptor sensitivity in the PVN and also enhances HPA function (290). Collectively, it seems that NA signaling from the A2 cell group to the hypothalamus and limbic forebrain contributes to mechanisms that support drug seeking and self-administration, increased anxiety during drug abstinence, altered reward processing (i.e., dysphoria), and the general relationship between the use of mood-altering drugs and mood disorders (12, 38, 78, 131, 176, 244).…”