This is a request for a NIDA Mentored Research Career Award (KO1) to study the candidate's interest in the role of L-type Ca2+ channels in amphetamine-mediated CREB phosphorylation and dynorphin gene expression. Much of the progress in substance abuse research has focused on the neuro- and behavioral pharmacology of drugs of abuse. However only recently the significance of the molecular changes associated with chronic drug use are being unraveled. Towards a better understanding of the addictive properties of these drugs, the candidate will apply her molecular biology background to study the molecular mechanisms underlying addictive behavior. As a research fellow, the candidate has gained knowledge and received training in the molecular mechanism of the dopamine signal transduction pathway in primary striatal cultures. The in vitro studies indicate a dependence of dopamine-mediated CREB phosphorylation and gene expression on L-type Ca2+ channels. This is highly relevant because of the recent implication of L-type Ca2+ channels in psychostimulant-induced behavior. Through this award the candidate will correlate the molecular events observed in vitro to an in vivo model of chronic amphetamine, in rats. The role of L-type Ca2+ channels in amphetamine-mediated CREB phosphorylation and dynorphin gene expression will be examined. Both CREB and dynorphin have been directly implicated in the addictive properties of the psychostimulant, cocaine. The candidate's training has primarily been in in vitro and cell cultures systems. Through this award she will further expand her repertoire of training to in vivo work. The training received through this award will include learning the neuroanatomy, neuropharmacology and behavioral effects of psychostimulant abuse. In particular the candidate will learn (1) in situ hybridization in brain slices (2) stereotaxic surgeries to introduce drugs, antisense oligonucleotides and viral vectors directly into the brain, (3) viral vector technology, a powerful new method to manipulate neuronal function, and (4) test locomotor activity.
