Psychiatric/emotional disturbances such as aggression and depression affect a significant proportion of patients with Alzheimer's disease (AD). There is evidence outlined in this proposal that abnormalities in the serotonergic and noradrenergic neurotransmitter systems underlie these behavioral derangements; and that a shared common endpoint for the therapeutic effects of antidepressant compounds and other interventions for the treatment of these patients could be the regulation of brainderived neurotrophic factor (BDNF). Antidepressant medications, commonly prescribed treatments of choice for aggression/agitation and depression, have been shown to up-regulate BDNF mRNA in the hippocampus of chronically treated rats. A number of clinical studies have suggested that physical exercise significantly improves emotional status as well as cognitive function in elderly patients. This simple behavior, physical exercise, has been shown, in our own Institute, to lead to rapid BDNF mRNA induction in the rat brain. We hypothesize that BDNF regulation is a common result of each of these interventions, and that the responses to physical activity and antidepressant treatment are synergistic. Our preliminary results, outlined in this proposal, indicate that a combination of antidepressant drug treatment and general physical activity potentiates the level of BDNF mRNA within the adult rat hippocampus in an additive manner. We wish to further characterize this combined effect, and to determine its time course and dose-reponse in the aging brain. Following this characterization, we wish to test the hypothesis that the BDNF induction brought about by antidepressant treatment, physical activity or the combination takes place through noradrenergic and/or serotonergic systems, and to determine which of these is most vital to maintain the observed effect. We also wish to test the hypothesis that synaptic protein changes downstream of BNDF induction result from these interventions. The proposed experiments will provide information about the mechanism of drug treatments for depression and aggression; leading to the development of better, more specific interventions for emotional dyscontrol in AD and other neurodegenerative disorders of the elderly. It is proposed that emotional management in dementia can be improved by physical activity in conjunction with antidepressant agents.
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