Because of high incidence of cigarette smoking among depressed individuals, it has been postulated that[unreadable] smoking may reflect an attempt at self-medication with nicotine by these individuals. However, other studies[unreadable] suggest that smoking may precede depression. Recent findings by us and others depict a complex[unreadable] involvement of nicotine and nicotinic system in mood regulation. Thus, nicotine acutely or chronically may[unreadable] act as an antidepressant in Fliners Sensitive Line (FSL) rats, a strain with inherent depressive-like behavior.[unreadable] However, in WKY rats, another putative animal model of depression, depending on the administered[unreadable] regimen, nicotine may act as an antidepressant or a "depressogenic" agent by exacerbating the depressive[unreadable] characteristics of these rats. Hence, the questions of when and how nicotine may act as an antidepressant[unreadable] or a depressogenic or what central mechanisms may mediate its effects remain unanswered. Recent[unreadable] findings strongly suggest that the brain-derived neurotrophic factor (BDNF) may be a common denominator[unreadable] in the mechanism of action of all antidepressants. Hence, the major aim of this proposal is to elucidate the[unreadable] interactions between nicotine, BDNF and its high affinity receptor Trk-B in relation to depression. Specifically,[unreadable] the following hypotheses will be evaluated: 1. Antidepressant effects of nicotine will be associated with an[unreadable] increase in BDNF and Trk-B densities in hippocampal and other areas implicated in mood regulation, and[unreadable] the "depressogenic" effects of nicotine will be associated with an opposite effect on these parameters. 2. The[unreadable] antidepressant effects of nicotine will be associated with an anti-apoptotic activity and depressogenic effects[unreadable] of nicotine will be associated with a pro-apoptotic activity. 3. Clinically effective antidepressants that are also[unreadable] effective in this model will increase BDNF, Trk-B and antiapoptotic activities. 4. Clinically effective[unreadable] antidepressants that are not effective in this model will not affect BDNF or apoptotic activities. 5. Serum[unreadable] BDNF levels will be decreased in depressive states and effective antidepressants will elevate serum BDNF[unreadable] levels. Behavioral analyses will include Porsolt forced swim test and general locomotor activity. BDNF and[unreadable] TrkB containing neurons will be quantified by immunocytochemical and state of the art stereological[unreadable] techniques. TUNEL staining and stereological quantification will be applied to determine the extent of[unreadable] apoptosis. Enzyme-linked immunosorbent assay (ELISA) will be used to quantify the serum levels of BDNF.[unreadable] The results of these studies can: 1. provide answers to the seemingly contradictory effects of nicotine on[unreadable] mood, 2. indicate a common determinant for antidepressant effectiveness, and 3. suggest a possible[unreadable] peripheral marker for the depressive state and/or efficacy of antidepressant treatments. The findings may[unreadable] also facilitate the development and evaluation of novel antidepressants and/or compounds useful in smoking[unreadable] cessation.