Nicotine withdrawal induces subsensitivity of hypothalamic-pituitary-adrenal axis to stress in rats: implications for precipitation of depression during smoking cessation.

Epidemiologic studies show that smokers with a past history of depression are more likely to relapse into depression after smoking cessation than those without a history of depression. These studies suggest the existence of a direct biological link between nicotine withdrawal and depression. To investigate the neuronal and hormonal mechanisms of the precipitation of depression during smoking cessation, we used an animal model of nicotine withdrawal and studied the function of the hypothalamic-pituitary-adrenal (HPA) axis, the abnormality of which is implicated in the pathogenesis of depression. Rats were implanted with a minipump delivering nicotine at 6.0 mg/kg/day for 12 days. The minipumps were removed in order to abruptly terminate nicotine infusion. The activity of the HPA axis was determined on day 2 of withdrawal using the stress-induced corticosterone response and the dexamethasone suppression test (DST). At the same time the expressions of glucocorticoid receptor (GR) mRNA in the hippocampus and paraventricular nucleus of hypothalamus (PVN) and corticotropin-releasing hormone (CRH) mRNA in PVN were determined by non-radioactive in situ hybridization. Nicotine withdrawal resulted in lower corticosterone levels during restraint stress, suggesting subsensitivity of the HPA axis to stress. The result of DST, however, did not show a significant difference between nicotine-withdrawal and control rats. These effects of nicotine withdrawal were not accompanied by any changes in the expressions of GR and CRH mRNA in either hippocampus or PVN. These results suggest that subsensitivity of the HPA axis to stress during nicotine withdrawal may be implicated in the precipitation of depression during smoking cessation, although GR and CRH in the HPA axis do not appear to play a significant role.