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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
7R01MH059776-02
Application #
6156825
Study Section
Special Emphasis Panel (ZRG1-BDCN-6 (01))
Program Officer
Brady, Linda S
Project Start
1999-04-01
Project End
2004-03-31
Budget Start
1999-09-28
Budget End
2000-03-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
California State University Los Angeles
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90032
Chen, Michael J; Russo-Neustadt, Amelia A (2009) Running exercise-induced up-regulation of hippocampal brain-derived neurotrophic factor is CREB-dependent. Hippocampus 19:962-72
Arunrut, Teda; Alejandre, Hilda; Chen, Michael et al. (2009) Differential behavioral and neurochemical effects of exercise, reboxetine and citalopram with the forced swim test. Life Sci 84:584-9
Haack, Danielle; Luu, Henry; Cho, Jaehoon et al. (2008) Exercise reverses chronic stress-induced Bax oligomer formation in the cerebral cortex. Neurosci Lett 438:290-4
Chen, Michael J; Russo-Neustadt, Amelia A (2007) Nitric oxide signaling participates in norepinephrine-induced activity of neuronal intracellular survival pathways. Life Sci 81:1280-90
Chen, Michael J; Russo-Neustadt, Amelia A (2007) Running exercise- and antidepressant-induced increases in growth and survival-associated signaling molecules are IGF-dependent. Growth Factors 25:118-31
Chen, Michael J; Ivy, Autumn S; Russo-Neustadt, Amelia A (2006) Nitric oxide synthesis is required for exercise-induced increases in hippocampal BDNF and phosphatidylinositol 3' kinase expression. Brain Res Bull 68:257-68
Chen, Michael J; Russo-Neustadt, Amelia A (2005) Exercise activates the phosphatidylinositol 3-kinase pathway. Brain Res Mol Brain Res 135:181-93
Russo-Neustadt, Amelia A; Alejandre, Hilda; Garcia, Celithelma et al. (2004) Hippocampal brain-derived neurotrophic factor expression following treatment with reboxetine, citalopram, and physical exercise. Neuropsychopharmacology 29:2189-99
Garza, Antonio A; Ha, Tony G; Garcia, Celithelma et al. (2004) Exercise, antidepressant treatment, and BDNF mRNA expression in the aging brain. Pharmacol Biochem Behav 77:209-20
Garcia, C; Chen, M J; Garza, A A et al. (2003) The influence of specific noradrenergic and serotonergic lesions on the expression of hippocampal brain-derived neurotrophic factor transcripts following voluntary physical activity. Neuroscience 119:721-32

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