This project continues studies on the effects of an environmental stressor, randomly presented loud sound, on biochemical indices of the function of the rostrally projecting midbrain 5-hydroxytryptamine (5-HT, serotonin) containing neurons of rat brain. Their activation is monitored by the in vitro activity of tryptophan hydroxylase, the enzyme at is rate-limiting in the synthesis of the transmitter (modulator) 5-HT and thus determines 5-HT availability. This enzyme exhibits two distinct changes in activity to acute or repeated sound stress, 1) a rapidly reversible increase in activity that is abolished in vitro with alkaline phosphatase and 2) a more persistent increase in enzyme activity seen only after repeated sound stress that is insensitive to the action of alkaline phosphatase. Both increases in activity require the presence of glucocorticoid and are mediated over the amygdaloid central nucleus (ACE). In addition, corticotropin releasing factor (CRF) is known to be involved in the response to acute sound stress. The goal is to explore further the neural pathways, neurotransmitters (modulators) that mediate the appearance of the two types of increase in enzyme activity as well as the involvement of steroid hormones. Studies will focus on the ACE and associated lateral bed nucleus of the stria terminalis, their caudal projections as well as known synaptic inputs to the midbrain raphe and the type I and II corticosterone receptors of brain. Localized stereotaxic microinfusions of CRF, other peptides or classical transmitters, their antagonists, and of steroids and steroid antagonists, or discrete lesions (made by radiofrequency, ibotenic acid or the neurochemically selective neurotoxins, 6-hydroxydopamine or 5,7-dihydroxytryptamine) will be used to identify the neuroanatomical and chemical substrates of the 5-HT response to sound stress. HPLC-EC is used to quantitate 5-hydroxytryptophan (5-HTP) formed in the enzyme assay, tissue levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid, and tissue 5-HTP accumulation after inhibition of decarboxylation in vivo. The molecular mechanisms that may mediate the two changes in enzyme activity namely phosphorylation or an increase in enzyme level will also be explored with an antibody to the enzyme. These studies may have relevance for severe depression, a condition that can be triggered by stress and in which altered levels of 5-HT, CRF and plasma glucocorticoid have been implicated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS014090-11
Application #
3395394
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1979-12-01
Project End
1994-08-31
Budget Start
1991-09-01
Budget End
1992-08-31
Support Year
11
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
Corley, Karl C; Phan, Tam-Hao; Daugherty, Wilson P et al. (2002) Stress-induced activation of median raphe serotonergic neurons in rats is potentiated by the neurotensin antagonist, SR 48692. Neurosci Lett 319:1-4
Dilts, R P; Novitzki, M R; Phan, T H et al. (1996) Neurotensin inhibits the activation of midbrain serotonergic neurons produced by random inescapable sound. Brain Res 742:294-8
Dilts, R P; Boadle-Biber, M C (1995) Differential activation of the 5-hydroxytryptamine-containing neurons of the midbrain raphe of the rat in response to randomly presented inescapable sound. Neurosci Lett 199:78-80
Singh, V B; Kalimi, M; Phan, T H et al. (1994) Intracranial dehydroepiandrosterone blocks the activation of tryptophan hydroxylase in response to acute sound stress. Mol Cell Neurosci 5:176-81
Singh, V B; Corley, K C; Krieg, R J et al. (1994) Sound stress activation of tryptophan hydroxylase blocked by hypophysectomy and intracranial RU 38486. Eur J Pharmacol 256:177-84
Boadle-Biber, M C (1993) Regulation of serotonin synthesis. Prog Biophys Mol Biol 60:1-15
Boadle-Biber, M C; Singh, V B; Corley, K C et al. (1993) Evidence that corticotropin-releasing factor within the extended amygdala mediates the activation of tryptophan hydroxylase produced by sound stress in the rat. Brain Res 628:105-14
Corley, K C; Singh, V B; Phan, T H et al. (1992) Effect of gepirone on increases in tryptophan hydroxylase in response to sound stress. Eur J Pharmacol 213:417-25
Singh, V B; Hao-Phan, T; Corley, K C et al. (1992) Increase in cortical and midbrain tryptophan hydroxylase activity by intracerebroventricular administration of corticotropin releasing factor: block by adrenalectomy, by RU 38486 and by bilateral lesions to the central nucleus of the amygdala. Neurochem Int 20:81-92
Singh, V B; Onaivi, E S; Phan, T H et al. (1990) The increases in rat cortical and midbrain tryptophan hydroxylase activity in response to acute or repeated sound stress are blocked by bilateral lesions to the central nucleus of the amygdala. Brain Res 530:49-53

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