Major depressive illness is alleviated by chronic but not acute administration of antidepressant drugs or electroconvulsive therapy. Although the biochemical mechanisms of antidepressant action are not clearly understood, the delay in the therapeutic efficacy of these treatments has led to the hypothesis that some adaptive alteration in neuronal function must occur over time. The most consistent adaptive- biochemical effect of chronic antidepressant treatment in experimental animals is a down-regulation of the B-adrenergic receptor (BAR)-coupled adenylate cyclase system. This system is also regulated by pituitary- adrenal hormones and clinical investigations have indicated that there is a dysfunction of this hormone system in many depressed patients. Taken together these findings suggest that a pituitary-adrenal hormone imbalance may contribute to the biochemical alterations which underlie depression. The long-term objective of this research proposal is to extend previous work beyond the level of receptor binding sites and second messengers by studying antidepressant and pituitary-adrenal hormone regulation of BARs and G proteins at the level of gene expression. The regulation of BARs and G protein messenger RNA by antidepressant and hormone treatment will be determined by Northern blot analysis using specific cDNA probes while the levels of G protein subunits will be studied by quantitative immunolabeling and ADP- ribosylation. Preliminary studies have demonstrated that chronic imipramine treatment regulates the level of BAR mRNA while both antidepressant and glucocorticoid administration differentially regulate the levels of message and protein for specific G protein subunits. These effects will be further investigated and extended to an examination of their time dependence, pharmacology and regional specificity and the rate of gene transcription will be directly examined by nuclear runoff assays. Finally, neurotransmitter receptor-G protein regulation of adenylate cyclase will be studied to access the physiological relevance of the antidepressant and hormone induced alterations. These studies could elucidate the adaptive-molecular mechanisms which mediate antidepressant therapy as well as the role of pituitary-adrenal hormones in the etiology of depression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29MH045481-05
Application #
3475318
Study Section
Neurosciences Research Review Committee (BPN)
Project Start
1989-09-01
Project End
1994-08-31
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
5
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Duman, Ronald S; Aghajanian, George K; Sanacora, Gerard et al. (2016) Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med 22:238-49
Duman, Ronald S; Aghajanian, George K (2014) Neurobiology of rapid acting antidepressants: role of BDNF and GSK-3?. Neuropsychopharmacology 39:233
Voleti, Bhavya; Navarria, Andrea; Liu, Rong-Jian et al. (2013) Scopolamine rapidly increases mammalian target of rapamycin complex 1 signaling, synaptogenesis, and antidepressant behavioral responses. Biol Psychiatry 74:742-9
Duric, Vanja; Banasr, Mounira; Stockmeier, Craig A et al. (2013) Altered expression of synapse and glutamate related genes in post-mortem hippocampus of depressed subjects. Int J Neuropsychopharmacol 16:69-82
Newton, Samuel S; Fournier, Neil M; Duman, Ronald S (2013) Vascular growth factors in neuropsychiatry. Cell Mol Life Sci 70:1739-52
Duman, Ronald S; Li, Nanxin (2012) A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists. Philos Trans R Soc Lond B Biol Sci 367:2475-84
Fournier, Neil M; Lee, Boyoung; Banasr, Mounira et al. (2012) Vascular endothelial growth factor regulates adult hippocampal cell proliferation through MEK/ERK- and PI3K/Akt-dependent signaling. Neuropharmacology 63:642-52
Duman, Ronald S; Voleti, Bhavya (2012) Signaling pathways underlying the pathophysiology and treatment of depression: novel mechanisms for rapid-acting agents. Trends Neurosci 35:47-56
Fournier, Neil M; Duman, Ronald S (2012) Role of vascular endothelial growth factor in adult hippocampal neurogenesis: implications for the pathophysiology and treatment of depression. Behav Brain Res 227:440-9
Son, Hyeon; Banasr, Mounira; Choi, Miyeon et al. (2012) Neuritin produces antidepressant actions and blocks the neuronal and behavioral deficits caused by chronic stress. Proc Natl Acad Sci U S A 109:11378-83

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