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 idenify 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 wil determine the contribution of T-type channels to seizures resulting from multiple ethano 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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA016852-09
Application #
9257252
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Cui, Changhai
Project Start
2008-07-10
Project End
2019-03-31
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
9
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Dobbins, Dorothy L; Klorig, David C; Smith, Thuy et al. (2018) Expression of channelrhodopsin-2 localized within the deep CA1 hippocampal sublayer in the Thy1 line 18 mouse. Brain Res 1679:179-184
Rowland, Jared A; Stapleton-Kotloski, Jennifer R; Alberto, Greg E et al. (2017) Contrasting Effects of Posttraumatic Stress Disorder and Mild Traumatic Brain Injury on the Whole-Brain Resting-State Network: A Magnetoencephalography Study. Brain Connect 7:45-57
Rowland, Jared A; Stapleton-Kotloski, Jennifer R; Alberto, Greg E et al. (2017) Changes in nonhuman primate brain function following chronic alcohol consumption in previously naïve animals. Drug Alcohol Depend 177:244-248
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
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
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
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
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

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