The Drug Abuse Research Center brings together laboratory groups with varied interests in the neurobiological substrata for the actions of drugs of abuse, ranging from basic studies on the molecular and cell biological aspects of receptor, peptide and neurotransmitter synthesis and function, to the effects of drugs of abuse on the expressio of rapidly and more slowly responding neuronal genes. The Center will utilize a variety of experimental approaches to coordinate the activities of the four investigators on the theme of the dynamics of signal transduction for molecular messengers relevant to actions of drugs of abuse. Snyder will explore three principal areas of signal transduction (I) nitric oxide as a mediator of neurotoxicity, (2) neural functions of heme oxygenase-2, (3) novel regulatory proteins in the pineal gland with a particular focus upon serotonin N-acetyltransferase and pineal night-specific ATPase (PINA). Eipper will use proopiomelanocortin- producing pituitary melanotropes to study D2-dopamine receptor regulated transcripts that play a role in the response of peptidergic neurons to chronic treatment with dopamihergic agonists or antagonists. The similarities of peptidyllycine a-amidating monooxygenase (PAM) and dopamine b-monooxygenase (DBM), homologous copper, ascorbate and molecular oxygen-dependent enzymes essential to the formation of neuropeptides and catecholamines, will be used to understand better their function in large dense core vesicles. Mains will use chimeric proteins to study the routing of prohormone convertases, key enzyrnes in the production of neuropeptides, to larg dense core vesicles, and the influence of various regions of the prohormone convertases on the function of the enzymatic domains. Heart cell cultures will be employed as an example of a tissue containing mostly immature large dense core vesicles whose ability to perform endoproteolytic processing of prohormones and proteins can be manipulated using adenoviruses. The rules governing the trafficking of large and small dense core vesicles to the correct axonal or dendritic destination will be examined using cultures of sympathetic neurons, and manipulated using adenoviral vectors encoding peptide processing enzymes. Baraban will study the regulation of the Egr family of transcription factors in brain neurons: As these immediate early genes are robustly induced by synaptic stimulation and pharmacological agents including psychostimulants, they are likely to orchestrate changes in gene transcription underlying long-term effects of drug treatment. In addition, he will conduct studies aimed at identifying a novel """"""""brain-specific"""""""" factor that binds to the Egr DNA consensus sequence.
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