Sex differences in norepinephrine action in striatal neurons

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DESCRIPTION (provided by applicant): Drug addiction has an enormous toll on personal, family and public life. Understanding the physiological mechanisms underlying drug addiction pathologies and normal striatal function will ultimately reduce the societal and personal cost of drug abuse, making the neurobiology of drug abuse a relevant line of research. While the neuromodulator dopamine is the focus of most research in this area, evidence is accumulating that norepinephrine also plays an essential role in aspects of drug addiction. Our pilot data indicates that norepinephrine acts directly on striatal neurons cultured from the nucleus accumbens and dorsal striatum to phosphorylate cAMP Response Element Binding Protein (CREB), a transcription-factor directly implicated as a molecular switch underlying long-term effects of drug abuse on the brain. We will build on this result in the first aim of our proposal, where we will elucidate the underlying signal transduction pathway that norepinephrine activates, and test whether this pathway induces gene expression. One of the most interesting aspects of drug addiction is that it is sexually dimorphic. There is currently not a clear mechanism to account for sex differences in drug abuse behavior. Interestingly, we find that the ¿1- adrenergic receptor is sexually dimorphic in adult striatum. In the second aim of our proposal we test the extent of this sexual dimorphism in NE action and whether it is induced via early hormone exposure. Finally, this proposal contains a significant training component. My ultimate career goal is to be a principal investigator at a research university. As a professor at such an institution, I want my research program to investigate phenomena of societal importance and to encompass techniques ranging from the molecular to the behavioral. The training that I will receive from this NRSA will help provide necessary background to meet these career goals. I will be trained in the usage of molecular and cellular neurobiological techniques, and broaden my research portfolio into mechanisms underlying drug abuse, sex differences, and the molecular physiology of mammalian striatal neurons. PUBLIC HEALTH RELEVANCE: Drug addiction is believed to be triggered by alterations in striatal monoamine signaling. Most research has focused on the role of dopamine, but accumulating evidence also suggests a strong norepinephrine component. In this proposal, we will test whether norepinephrine can directly affect molecular events related to drug addiction. Preliminary data suggest that norepinephrine action is sexually dimorphic. We will determine the extent of this dimorphism and test whether it is induced via early hormone exposure. The sex difference in norepinephrine signaling provides a potential mechanism underlying sexual dimorphisms in drug addiction behavior.