Recent clinical studies indicate that patients' symptoms disappear gradually during continuous antidepressant (AD) treatment. Data from our laboratory indicate there are regional brain differences in the rate of adrenergic receptor adaptation during chronic AD administration. These data may provide evidence that the gradual improvement in the symptoms of depressive illness during chronic AD treatment is due to the recruitment of successive brain areas where receptor adaptation has occurred. Consequently, one hypothesis to be tested in this grant is that regional brain differences in the rate of adrenergic receptor adaptation are common to AD treatments. Data relevant to this hypothesis will be obtained by examining effects of ADs from different chemical classes on beta- and alpha-adrenergic receptor (AR) adaptation at several different times during chronic AD treatment. This biochemical study will be complemented by an electrophysiological study evaluating sensitivity of alpha- and beta-ARs. A second seminal finding by our laboratory is that stress facilitates receptor adaptation produced by ADs while chronic AD treatment attenuates specific cellular responses to stress. Thus, the second hypothesis proposed is that the facilitation of AD action by stress and the antagonism of specific functional responses to stress by chronic AD treatment are also common to ADs. To test the first part of this hypothesis, we will determine whether combining AD treatment with forced swim will accelerate AD-induced adaptation of beta-ARs in regions where receptor adaptation is delayed. If facilitation is found, this would suggest that a component of stress can facilitate neural adaptation produced by ADs. The second portion of this hypothesis will extend our observation that chronic imipramine (IMP) treatment reduces the number of cells exhibiting c-fos-like immunoreactivity (c-FLI) in PVN and medial prefrontal cortex after forced swim. We will determine if ADs from several classes share this action with IMP on the swim stress-induced changes in c-FLI. Swim stress can also increase spontaneous LC activity. Consequently, we also will determine whether chronic AD administration will affect this stress-induced increase in LC firing as well as define neural activity in the PVN and the medial prefrontal cortex after stress. This multidisciplinary grant provides a new theoretical position concerning neural adaptation caused by chronic AD treatment that depends on an integration of time, brain region, and the specific AD administered, as well as the ability of ADs to modify responses to stress. Completion o these studies will provide specific data relevant to the two major hypotheses proposed to explain AD action and will expand our knowledge about the specific neuroanatomical sites at which ADs influence CNS function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH039144-07A1
Application #
3377125
Study Section
Neuropharmacology and Neurochemistry Review Committee (NPNC)
Project Start
1984-02-01
Project End
1997-11-30
Budget Start
1992-12-01
Budget End
1993-11-30
Support Year
7
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Duncan, G E; Knapp, D J; Carson, S W et al. (1998) Differential effects of chronic antidepressant treatment on swim stress- and fluoxetine-induced secretion of corticosterone and progesterone. J Pharmacol Exp Ther 285:579-87
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Duncan, G E; Johnson, K B; Breese, G R (1993) Topographic patterns of brain activity in response to swim stress: assessment by 2-deoxyglucose uptake and expression of Fos-like immunoreactivity. J Neurosci 13:3932-43
Duncan, G E; Little, K Y; Kirkman, J A et al. (1992) Autoradiographic characterization of [3H]imipramine and [3H]citalopram binding in rat and human brain: species differences and relationships to serotonin innervation patterns. Brain Res 591:181-97
Duncan, G E; Little, K Y; Koplas, P A et al. (1991) Beta-adrenergic receptor distribution in human and rat hippocampal formation: marked species differences. Brain Res 561:84-92
Duncan, G E; Paul, I A; Fassberg, J B et al. (1991) Autoradiographic analysis of the in vivo distribution of 3H-imipramine and 3H-desipramine in brain: comparison to in vitro binding patterns. Pharmacol Biochem Behav 38:621-31
Paul, I A; Duncan, G E; Mueller, R A et al. (1991) Neural adaptation in response to chronic imipramine and electroconvulsive shock: evidence for separate mechanisms. Eur J Pharmacol 205:135-43

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