Mental illness is often associated with changes in endocrine status. However, little is known about the relationships between hormones and brain neurochemistry, in particular neurotransmitter receptor function. This research project consists of a series of studies aimed at examining these questions. Thus, preliminary data are described which suggest that ACTH administration modulates the number, affinity, and function of GABA, Beta-adrenergic and serotonin2 receptors in brain, and receptor resonses to antidepressant drugs. Experiments will be undertaken to better characterize the multiplicity of GABA binding sites in brain by assessing radioligand attachment in the presence of various inorganic ions, and at different temperatures, to determine whether these sites are pharmacologically and kinetically distinct. Also, the anatomical location of the different GABA binding sites will be determined by performing brain lesion studies. Once the various sites have been classified, the influence of ACTH and other peptide hormones on the different populations of GABA binding sites will be determined. Furthermore, studies are described to define the relationship between hormones and the receptor responses to antidepressants, as well as to elucidate the molecular events associated with receptor regulation. Thus, data are presented to indicate that co-administration of ACTH with some antidepressants causes a more rapid change in receptor number and function than is observed with the antidepressant alone. It has also been found that ACTH treatment, by itself, modifies Beta-adrenergic receptor activity in the brain. By examining the influence of the hormone and drug treatments on the various components of the Beta-adrenergic receptor-coupled cyclic nucleotide system (recognition site, G/F protein, cyclase, phosphodiesterase) it may be possible to better understand the mechanism of these interactions at the molecular level. To this end, receptor binding assays, regulatory protein extraction and reconstitution assays, and cyclase assays will be utilized. The results of these studies should provide new information about the molecular mechanisms that regulate receptor responses to drugs and hormones, and thereby yield insights into the mode of action of antidepressants and into the etiology and treatment of affective illness and other mental disorders.
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