A coordinated set of experiments is proposed to study the effects of drugs of abuse on gene regulation in the rat striatum. The experiments are based on evidence from the PI's laboratory and other laboratories suggesting that amphetamine, cocaine and morphine induce specific patterns of immediate-early gene (IEG) regulation in the caudoputamen and nucleus accumbens by signaling pathways that use D1-like receptor mediation. The proposed experiments are divided into three parts, which are aimed at: (1) extensively characterizing the acute effects of these drugs in terms of cell types and IEG gene and neuropeptide genes affected in the striatum, and the other brain regions that might be involved in the induction in the striatum; (2) examining the effects of chronic continuous and intermittent drug exposure on IEG and neuropeptide gene induction, and the patterns of dopamine afferent toxicity found with high dose exposure; and (3) characterizing the prenatal and postnatal effects of these drugs on IEG and peptide gene induction in the striatum. We will rely on immunocytochemistry, in situ hybridization and Northern blotting to analyze the brains. The significance of the data to be obtained is that they should permit extremely detailed identification of the types of neurons responding transcriptionally to these drugs and an inventory of genes regulated over short and long drug exposure. The patterns of regulation identified should lead to a better understanding of possible mechanisms underlying the powerful effects of these drugs on central nervous system function including long-term neural changes.
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