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Neurobiology of Migraine

Migraine is one of the most common disorders affecting the general population, resulting in a staggering amount of episodic disability and lost productivity worldwide. Despite the extraordinarily high prevalence of migraine, our understanding of its pathophysiology is incomplete. Moreover, while there has been significant progress in the acute treatment of migraine attacks, the ability to treat frequent and chronically disabling migraine, remains severely limited. There continue to be millions of individuals for whom currently available migraine therapies are either ineffective or poorly tolerated.

A significant obstacle to the identification of new migraine therapies has been the lack of predictive animal models, and it has been particularly difficult to study the progression of migraine from an episodic to a chronic disorder. We have recently developed a novel chronic migraine model in mice using the known human migraine trigger, nitroglycerin. Our work shows that chronic intermittent treatment with nitroglycerin produces an acute and chronic hyperalgesia. This model is translationally significant, and prototypic acute and preventative anti-migraine therapies inhibited nitroglycerin-induced hypersensitivity. We are currently using this model to identify novel drug targes, and to characterize the mechanisms that result in the chronification of migraine. Amynah Pradhan, PhD 

Ligand Directed Signaling at Delta Opioid Receptors

Activation of the delta opioid receptor has been shown to produce pain-relief, and reduce anxiety and depression. For these reasons agonist to this receptor are currently being developed for clinical use.  However, a deterrent to the development of these compounds, is that some delta opioid receptor agonists also produce convulsions, an adverse effect that has been observed across species.  At the moment there is no way to predict whether a novel agonist will have this property. The goal of this work is to determine the mechanism that accounts for this difference between agonists that bind to the same receptor.  These studies have important biological implications, and ultimately would increase the potential for delta opioid receptor agonists as novel drug therapies.

Amynah Pradhan, PhD

Mechanisms of Estrogen Action in Enhancing Behavioral Responses to Cocaine

Females progress more rapidly to cocaine addiction and the sex hormone estrogen is thought to contribute to this process by enhancing the behavioral effects of cocaine. The goal of this project is to understand on a molecular level how estrogen increases behavioral responses to cocaine. The approach outlined in this proposal is to study the function of estrogen receptors and associated signaling molecules in female mice using two behavioral measures related to cocaine addiction, conditioned place preference and sensitization.

Amy W. Lasek, PhD

Regulation of Excessive Alcohol Consumption by the Lmo-Alk Axis

The goal of this project is to study the function of four genes in rodent models of binge drinking and alcohol dependence. The genes include Lmo3 and Lmo4, which encode transcriptional regulators, Alk, which encodes a receptor tyrosine kinase, and Mdk, which encodes a ligand that regulates the Alk gene product. Preliminary work suggests that these four genes cooperate to regulate behaviors associated with excessive alcohol consumption. The work will provide basic insights into the role of a new signaling pathway in controlling behaviors that model human alcohol abuse. In addition, some of the genes in the pathway are protein kinases, which are regarded as excellent targets for drug development. This project will thus lay the groundwork for development of novel pharmacotherapies for alcohol abuse in humans.

Amy W. Lasek, PhD

RNA Interference Core

This project is part of the Integrative Neuroscience Initiative on Alcoholism (INIA-West) Consortium funded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA). The goal of INIA-West is to identify the molecular, cellular, and behavioral changes that occur in specific brain regions that result in excessive alcohol consumption. The RNA Interference Core supports INIA-West Investigators in reaching this goal by providing the tools necessary to study the role of genes in the brain that contribute to excessive alcohol drinking.

Amy W. Lasek, PhD

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