This training plan proposal is focused on determining the cellular and molecular alterations of low-threshold, voltage-gated calcium channels (T-type) that occur within the thalamus after multiple ethanol withdrawals. By linking these changes to the development of progressively more severe withdrawal symptoms, I hope to understand the effects of ethanol withdrawal on thalamic function. Identifying treatments that then target these channels may therefore present new and effective pharmacotherapies in the successful rehabilitation of alcoholic patients. To address these issues will require new training in technical and conceptual approaches to alcohol withdrawal. I will accomplish this by investigating three integrated aims. The first two aims will be to determine how T-type calcium channels contribute to underlying neuronal changes in response to a multiple ethanol exposure and withdrawal mouse model.
In Aim 1, using real time RT-PCR, I will examine thalamic T-type channel gene expression levels in mice during and after multiple ethanol exposures in a vapor chamber. I hypothesize an increase in T-type channel gene expression during ethanol withdrawal, and that the degree of these increases will be directly related to the number of withdrawals.
In Aim 2, 1 will record whole cell T-type currents from midline thalamic neurons of mice exposed to multiple withdrawals. I hypothesize a concomitant, functionally relevant increase in T-type channel function, as well as alterations in channel kinetics which may underlie the increased susceptibility to seizures during ethanol withdrawal.
Aim 3 will be to determine the effects of the T-type calcium channel inhibitors ethosuximide and ascorbate during ethanol withdrawal. I will monitor cortical EEC activity using brief spindle episodes as a direct measure of neuronal excitability, thus providing an indirect measure of withdrawal seizure susceptibility. I hypothesize a reduction in the amount spindle incidents in mice that have been administered ethosuximide and ascorbate. Alcohol withdrawal syndrome is a significant societal problem. This research proposal is important because it will provide me with the necessary training to understand the long-term molecular and physiological changes that occur in response to chronic ethanol exposure and subsequent withdrawal. Current treatments for alcohol withdrawal, such as benzodiazepines, only address the immediate symptoms and can mask underlying physiological changes occurring during multiple withdrawals that can give rise to more severe symptoms. A more precise understanding of the mechanisms involved in the progression of alcohol withdrawal syndrome offers a tremendous opportunity for identifying new adjunct pharmacological interventions that can aid in the successful treatment of alcohol withdrawal patients.
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| Wiggins, Walter F; Graef, John D; Huitt, Tiffany W et al. (2013) Ethosuximide reduces ethanol withdrawal-mediated disruptions in sleep-related EEG patterns. Alcohol Clin Exp Res 37:372-82 |
| Graef, J D; Huitt, T W; Nordskog, B K et al. (2011) Disrupted thalamic T-type Ca2+ channel expression and function during ethanol exposure and withdrawal. J Neurophysiol 105:528-40 |
| Graef, John D; Godwin, Dwayne W (2010) Intrinsic plasticity in acquired epilepsy: too much of a good thing? Neuroscientist 16:487-95 |
| Graef, John D; Nordskog, Brian K; Wiggins, Walter F et al. (2009) An acquired channelopathy involving thalamic T-type Ca2+ channels after status epilepticus. J Neurosci 29:4430-41 |
