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