T-Channel Dysregulation during Alcohol Withdrawal: Mechanisms and Novel Therapies

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DESCRIPTION (provided by applicant): The primary objectives of this research training plan is to identify the molecular mechanisms responsible for T- type calcium channel (T-channel) dysregulation during alcohol withdrawal, and to determine whether T- channels can serve as preclinical therapeutic targets for alcohol withdrawal seizures. Withdrawal symptoms including seizures drive individuals to relapse, thus representing a significant barrier to recovery. With each successive withdrawal, symptoms increase in severity in a kindling-like phenomenon. Due to the depressing effects of alcohol in the CNS, compensatory mechanisms of progressive neuronal excitation ensue, with concurrent development of disrupted brain rhythms. Using an intermittent alcohol exposure paradigm, our lab has identified a disruption in the thalamic T-type calcium isoform, CaV3.2, during withdrawal that may underlie the generation and propagation of withdrawal seizures. The mechanisms responsible for the abnormal increases in excitability of T-channels are unknown, as well as whether or not pharmacological treatments targeting T-channels may be effective. I propose to address this potential mechanism at multiple levels. Specific Aim 1 will evaluate the use of ethosuximide, a non-specific T-channel antagonist, and the use of ascorbate, a specific CaV3.2 T-channel antagonist, as treatments against seizure acitivity during alcohol withdrawal. To further reveal mechanisms responsible for T-channel dysregulation during alcohol withdrawal, Aims 2 and 3 will evaluate if posttranslational modifications mediate the observed increase in excitability via protein kinase C (PKC) and the role of neuron-restrictive silencer factor (NRSF) in transcriptional regulation of CaV3.2 T-channel. This training plan proposed involves a multidisciplinary approach that will serve to advance the alcohol field by providing a better understanding of mechanisms and identifying novel targets for therapeutic intervention for individuals suffering from alcohol abus. This research approach will provide training in both electrophysiology and molecular techniques including surgical procedures, EEG analysis, patch clamp electrophysiology, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and Western blot techniques. With guidance and support from the advisor and research associates, this project will provide the necessary training to pursue questions that will provide insight into the serious conditions that develop after chronic alcohol abuse. PUBLIC HEALTH RELEVANCE: Alcohol withdrawal symptoms, including seizures, drive individuals to relapse and represent a significant barrier to recovery. Indentifying mechanisms responsible and novel therapeutic targets is critical to help individuals recovering from alcohol abuse and will lower the economic burden and fatality rates. Investigating T-channel dysregulation during alcohol withdrawal will not only help us understand mechanisms for increased hyperexcitability but may be a promising strategy for future pharmacological interventions.