Short-term exposure to stressful, aversive stimuli elicits a variety of adaptive physiological and behavioral responses, and chronic exposure to stress can evoke useful, adaptive responses as well. However, chronic exposure to stress also has been implicated in the development of many pathological conditions, including psychiatric disorders, and schizophrenia. In order to elucidate the central component of stress-induced abnormalities, the application will examine the impact of stress on central noradrenergic transmission, particularly the NE- containing neurons of the LC. Recently the investigators observed that exposure to chronic cold increased by 2-fold the ability of a subsequent acute stressor to release NE, a phenomenon that has been termed """"""""sensitization"""""""" when observed in other systems. However, little is known about the impact of chronic stress (i.e., as a result of its quality, intensity, and duration) or whether a given stress-induced change may be adaptive or maladaptive. Hence, the project proposes to systematically explore the relation between stress and its effects on LC neurons as well as the functional significance of those effects. In addition, it is planned to study the basic neurobiology of LC neurons, in particular, the nature of the heterosynaptic input to LC terminals and the rate of TH transport in these neurons.
Four specific aims are proposed: First, the impact of chronic stress on the synthesis and release of NE in response to a subsequent acute stress will be further characterized. Second, the mechanisms underlying these interactions will be examined by focusing on changes in NE synthesis, release, and inactivation, and by examining both autoreceptor and heteroreceptor input. Third, the application plans to explore the synthesis and transport of TH, the rate-limiting enzyme in NE synthesis. Finally, changes in the electrophysiology of LC neurons during acute and chronic stress will be investigated. The longer-term objectives of this project are to provide new insights into the basic neurobiology of LC neurons and the psychopathology that develops from chronic stress.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37MH029670-21
Application #
2413050
Study Section
Special Emphasis Panel (NSS)
Project Start
1977-06-01
Project End
2003-05-31
Budget Start
1998-06-03
Budget End
1999-05-31
Support Year
21
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Neurology
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Chang, M S; Sved, A F; Zigmond, M J et al. (2000) Increased transcription of the tyrosine hydroxylase gene in individual locus coeruleus neurons following footshock stress. Neuroscience 101:131-9
Wu, Y; Pearl, S M; Zigmond, M J et al. (2000) Inhibitory glutamatergic regulation of evoked dopamine release in striatum. Neuroscience 96:65-72
Zigmond, M J (1994) Chemical transmission in the brain: homeostatic regulation and its functional implications. Prog Brain Res 100:115-22
Kolibal-Pegher, S; Edwards, D J; Meyers-Schoy, S A et al. (1994) Adrenal medullary adaptations and cardiovascular regulation after 6-hydroxydopamine treatment in rats. J Auton Nerv Syst 48:113-20
Rassnick, S; Sved, A F; Rabin, B S (1994) Locus coeruleus stimulation by corticotropin-releasing hormone suppresses in vitro cellular immune responses. J Neurosci 14:6033-40
Baruchin, A; Vollmer, R R; Miner, L L et al. (1993) Cold-induced increases in phenylethanolamine N-methyltransferase (PNMT) mRNA are mediated by non-cholinergic mechanisms in the rat adrenal gland. Neurochem Res 18:759-66
Keefe, K A; Zigmond, M J; Abercrombie, E D (1993) In vivo regulation of extracellular dopamine in the neostriatum: influence of impulse activity and local excitatory amino acids. J Neural Transm Gen Sect 91:223-40
Miner, L L; Pandalai, S P; Weisberg, E P et al. (1992) Cold-induced alterations in the binding of adrenomedullary nuclear proteins to the promoter region of the tyrosine hydroxylase gene. J Neurosci Res 33:10-8
Vollmer, R R; Baruchin, A; Kolibal-Pegher, S S et al. (1992) Selective activation of norepinephrine- and epinephrine-secreting chromaffin cells in rat adrenal medulla. Am J Physiol 263:R716-21
Baruchin, A; Weisberg, E P; Miner, L L et al. (1990) Effects of cold exposure on rat adrenal tyrosine hydroxylase: an analysis of RNA, protein, enzyme activity, and cofactor levels. J Neurochem 54:1769-75

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