Major depression is often associated with elevated and flat glucocorticoid hormone levels, probably due to a diminished negative feed-back regulation of corticotropin releasing hormone (CRH). Moreover, the pathologic increase in glucocorticoid hormone secretion (Cushing's disease) is associated with major depression, which improves after the successful treatment of the endocrine disorder. The excess of glucocorticoid hormone secretion alters the activity of the brain's serotonergic (5-HT) system. Thus, clinical studies reported that depressed patients present a decreased binding capacity of 5-HT1A receptors, whereas various experimental studies reported a diminished function of 5- HT1A autoreceptors upon chronic administration of glucocorticoids. However, other experimental studies reported an inverse effect of chronic glucocorticoids, i.e., the increase in sensitivity of 5-HT1A autoreceptors. Nicotine produces antidepressant effects in both humans and animal models of depression, through the release of endogenous antidepressants such as noradrenaline, dopamine and serotonin. The prevalence of smoking in depressed patients is significantly higher than in the normal population, and various investigators consider smoking to be a form of auto medication in depression. Experiments performed in our laboratory indicated that nicotine, administrated in midbrain slices, increases the firing rate of 70- 80% 5-HT dorsal raphe nucleus (DRN) neurons, as well as 5-HT release inside the DRN. Approximately 20-30% DRN 5-HT neurons responded to nicotine administration with inhibition of the firing rate. The stimulatory effect of nicotine results from its direct, postsynaptic effects, as well as from its indirect, presynaptic effects (glutamate and noradrenaline release). The inhibitory effects of nicotine were due to an increased intra-raphe serotonin release. In order to determine if nicotine or analogs can serve as therapeutic tools for treating the depression induced by elevated glucocorticoid hormone levels, experiments were performed on Wistar rats that were adrenalectomized and implanted subcutaneously with a 70 mg corticosterone capsule each. This experimental model ensures high and stable levels of blood corticosterone levels. After two weeks of exposure to corticosterone, midbrain slices were obtained and the responses of 5-HT DRN neurons to nicotine were studied. In most 5-HT DRN neurons the responses to nicotine were inhibitory, due to an increased function of the 5-HT1A autoreceptors and/or an increased nicotine-induced 5-HT release. These results contradict previous ones obtained from nonadrenalectomized rats, and may be explained by a diminished transport of tryptophan across the blood-brain barrier in adrenalectomized rats. © 2017 Nova Science Publishers, Inc.