The center will employ biochemical, neuroanatomical and neurophysiological strategies to clarify neurobiological substrata for abusable drug action. Snyder will examine several areas with a special focus on three. Properties of peripheral benzodiazepine receptors will be elucidated. Enkephalin convertase will be characterized. Adenosine localization and interactions with central stimulant xanthines will be explored. In Mains' laboratory pituitary development will be examined to probe changes in proteolytic cleavages of pro-ACTH/endorphin in anterior pituitary corticotropes. The influence of prenatal exposure of drugs on postnatal pituitary development will be studied, to clarify abnormalities in tissue response to secretagogues and alterations in processing. The neurotransmitter plasticity of sympathetic neurons, hypothalamic neurons, and adrenal chromaffin cells will be studied in primary tissue cultures; the changes and interactions of the synthesis, accumulation, and secretion of neuropeptide Y, catecholamines, and acetylcholine will be examined in detail in the sympathetic and adrenal cultures. In Eipper's laboratory the ability of secretagogues to alter pro-ACTH/endorphin synthesis, processing and secretion in primary cultures of adult rat anterior and intermediate pituitary cells maintained in CSFM will be determined. Factors increasing the responsiveness of corticotropes and melanotropes in CSFM will be investigated. The overall effect of specific secretagogues on corticotropic tumor cells (CRF, cAMP, phorbol esters, dexamethasone) and melanotropes (dopaminergic agents) will be evaluated. Effects of secretagogues on protein synthesis will be determined. cDNA libraries from control cells will be screened by differential hybridization to cDNA probes from secretagogue treated cells focussing on gene products regulated in parallel with hormone. Baraban will examine the role of serotonin 5HT2 receptors in mediating actions of hallucinogens. He will characterize the pharmacology of several 5HT2 receptor mediated responses and then determine the activity of hallucinogens and related compounds in functional assays. He will also evaluate the role of 5HT2 receptors in tolerance to hallucinogens.
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