The main objectives of this project are to determine the roles of catecholamines in brain functions that regulate motor activity, neuroendocrine secretion, and autonomic function. In vivo microdialysis is used to monitor levels of monoamines and their metabolites in extracellular fluid in specific brain regions, with simultaneous measurements of arterial plasma levels of norepinephrine (NE), epinephrine (EPI), and ACTH. Microdialysis probes with an attached infusion microcannulae are used to introduce drugs or isotopically-labelled compounds and sample extracellular fluid in the same region. Brain lesions are made surgically or by use of toxins specific to particular cell types. HPLC and liquid scintillation spectrophotometry are used in assays of materials in the microdialysates and in situ hybridization used to examine brain regional levels of mRNA encoding CRH. In rats with unilateral striatonigral dopamine (DA) neurons destroyed with 6-OHDA, DA formation from locally perfused DOPA was detected but was less on the lesioned than on the intact side. Clorgyline (an inhibitor of MAO-A), augmented DA production from DOPA both on the lesioned and the intact side, whereas deprenyl (an inhibitor of MAO-B) had no effect. Neuroendocrine responses to a variety of stressors (handling, immobilization, subcutaneous formalin injection, insulin, hemorrhage, or cold) indicated stressor-specific patterns. For example, insulin-induced hypoglycemia evoked marked, correlated increases in EPI and ACTH levels, whereas cold exposure increased plasma NE levels disproportionately compared with ACTH responses, and hypotensive hemorrhage increased ACTH levels disproportionately compared with catecholamine responses. Administration of cortisol inhibited basal and immobilization stress-induced NE release and catecholamine synthesis in the paraventricular nucleus (PVN). After adrenalectomy, release was enhanced, and the effects of adrenalectomy were reversed by treatment with replacement doses of cortisol. Thus, central noradrenergic pathways ascending from medullary centers participate in feedback inhibition of HPA axis activity exerted by circulating glucocorticoids. After brainstem hemisection, which interrupts noradrenergic pathways from the A1 and A2 areas to the PVN, immobilization stress-induced NE release in the ipsilateral PVN was reduced much more than in the contralateral PVN, whereas NE release in the central nucleus of the amygdala was unaffected on either side. Both basal levels and stress-induced enhancement of PVN mRNA encoding CRH were diminished ipsilateral to the hemisection. Plasma ACTH responses to immobilization, however, were uninfluenced by brainstem hemisection. This indicates that there is sufficient CRH release from only one PVN to elicit an unimpaired ACTH response to immobilization.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Intramural Research (Z01)
Project #
1Z01NS002870-04
Application #
5203994
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
1995
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code