There are fundamental gaps in understanding how alcoholism leads to alcohol withdrawal syndrome, with its range of serious clinical symptoms, including profound seizures. Withdrawal seizures become progressively worse with each withdrawal, complicate treatment, and can be fatal. It is therefore vital to identify safe and effective treatment alternatives. Calcium channels may offer such an alternative for treatment. The long-range goal of this work is to better understand the cellular and molecular mechanisms underlying alcohol withdrawal. The immediate goals of this proposal are: 1) to define the cellular and molecular alterations in T-type Ca2+ channels that occur in response to multiple WDs~ 2) to link these changes to the development of seizure and other features of alcohol WD syndrome~ 3) to examine whether treatments targeting these channels are effective~ 4) to understand how the acute sensitivity of the T-channel isoform implicated in our studies relates to alcohol WD syndrome and seizures involving this same channel~ and 5) to determine how relevant brain circuitry is recruited into WD seizure. Guided by strong preliminary data and published findings, and enabled by an innovative method of studying WD seizures, the following specific aims will be pursued:
Aim 1 will determine how acute inhibition of T-type channels by ethanol leads to WD hyperexcitability. Using the finding that PKC mediates the acute inhibitory effect of ethanol, whole cell recordings will be used to test the hypothesis that PKC inhibitors will reveal a change in ethanol-mediated inhibition of T-type currents during WD.
Aim 2 will determine the contribution of T-type channels to seizures resulting from multiple ethanol withdrawals. Quantitative EEG recordings will be used to test whether T-type channel blockers will inhibit WD seizure and will protect against the progression of seizures due to multiple, intermittent WDs.
Aim 3 will determine the site of origin and propagation patterns of WD seizure. The progression of WD seizure will be characterized using in vivo, multisite recordings coupled with novel optogenetic activation of this network using channelrhodopsin 2. The studies are highly significant because of the vertically integrated investigation of the role of T-type calcium channels in alcohol withdrawal seizure, which is an enduring problem in the treatment of abstaining alcoholics. The principles of channel modulation and network involvement promise to extend to other neural systems that include these channels. The studies are innovative because they deliver a new optogenetic approach to studying WD seizures, which will be used to understand the progression of WD seizure in unprecedented detail, and a potential new therapy based on a current antiepileptic drug.
The proposed research is relevant to public health because the study of the basic mechanisms of seizure has broad applications to neurological disease, including numerous epilepsy types, substance abuse and withdrawal syndromes. The proposal has high translational value, and is relevant to the NIH mission to gain knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce the burdens of illness and disability.
|Riegle, Melissa A; Masicampo, Melissa L; Shan, Hong Qu et al. (2015) Ethosuximide Reduces Mortality and Seizure Severity in Response to Pentylenetetrazole Treatment During Ethanol Withdrawal. Alcohol Alcohol 50:501-8|
|Santos, Lucas; Opris, Ioan; Hampson, Robert et al. (2014) Functional dynamics of primate cortico-striatal networks during volitional movements. Front Syst Neurosci 8:27|
|Caulder, Erin H; Riegle, Melissa A; Godwin, Dwayne W (2014) Activation of group 2 metabotropic glutamate receptors reduces behavioral and electrographic correlates of pilocarpine induced status epilepticus. Epilepsy Res 108:171-81|
|Klorig, David C; Godwin, Dwayne W (2014) A magnetic rotary optical fiber connector for optogenetic experiments in freely moving animals. J Neurosci Methods 227:132-9|
|Stapleton-Kotloski, Jennifer R; Kotloski, Robert J; Boggs, Jane A et al. (2014) Localization of interictal epileptiform activity using magnetoencephalography with synthetic aperture magnetometry in patients with a vagus nerve stimulator. Front Neurol 5:244|
|Riegle, Melissa A; Masicampo, Melissa L; Caulder, Erin H et al. (2014) Ethosuximide reduces electrographical and behavioral correlates of alcohol withdrawal seizure in DBA/2J mice. Alcohol 48:445-53|
|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|
|Shan, Hong Qu; Hammarback, James A; Godwin, Dwayne W (2013) Ethanol inhibition of a T-type CaÂ²+ channel through activity of protein kinase C. Alcohol Clin Exp Res 37:1333-42|
|Alexander, G M; Graef, J D; Hammarback, J A et al. (2012) Disruptions in serotonergic regulation of cortical glutamate release in primate insular cortex in response to chronic ethanol and nursery rearing. Neuroscience 207:167-81|
|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|
Showing the most recent 10 out of 15 publications