Sleep perturbations by ethanol play a key role in the progression of alcoholism, and are predictive of relapse. For some insomniacs, the sedative effects of ethanol are the pathway to bedtime alcohol consumption and eventual abuse. Continued abuse of ethanol leads to long-term changes in sleep circuitry that last well beyond the cessation of ethanol administration. The overall goal of this project is to determine the key molecular events that underlie cellular adaptation of sleep circuitry to alcohol, with the eventual goal of identifying novel drug targets for treatment of ethanol's disruption of normal sleep. The thalamus is a primary generator of sleep/wake cycles and the brain rhythms that occur during sleep. The best understood of these rhythms is the thalamic spindle oscillation associated with Stage II sleep, which is enhanced in response to acute alcohol administration. In alcoholics, spindle waves are diminished and are replaced with less-restful random eye movement (REM) sleep. Understanding the fate of spindle wave sleep is thus a vital question that directly relates to the reinforcement effects of ethanol, since some alcoholics return to drinking in an effort to improve the quality of their sleep. No laboratory has addressed the mechanism of these changes in a primate model, or in animals with well-characterized drinking schedules. The engine that allows spindle waves to flow through the brain is a low threshold calcium current, mediated by T-type calcium channels that come in three known varieties. We have recently shown that the T-channel transcript found in thalamic relay cells is exquisitely sensitive to ethanol, showing acute enhancement at the low end of physiologically meaningful ethanol concentrations (10-17mM). Amazingly, this current appears to be inhibited by concentrations of ethanol much above this range.
In Aim 1 of this project we will determine whether the T channel is functionally impaired in the dorsal lateral geniculate nucleus of chronic drinking animals by performing whole cell patch recordings in two preparations, monkeys and rats, in a condition of excessive drinking and in a condition near the peak of withdrawal.
In Aim 2, we will determine with patch recordings whether the T channel function is reduced in the thalamic reticular nucleus of chronic drinking animals. The experiments of Aim 3 will provide a complementary examination of the molecular expression patterns of T-type channels in monkeys and rats using quantitative RT-PCR techniques.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory Grants (P20)
Project #
5P20AA011997-08
Application #
7279984
Study Section
Special Emphasis Panel (ZAA1)
Project Start
Project End
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
8
Fiscal Year
2006
Total Cost
$107,625
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Type
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Davenport, April T; Grant, Kathleen A; Szeliga, Kendall T et al. (2014) Standardized method for the harvest of nonhuman primate tissue optimized for multiple modes of analyses. Cell Tissue Bank 15:99-110
Laudenslager, Mark L; Natvig, Crystal; Corcoran, Christopher A et al. (2013) The influences of perinatal challenge persist into the adolescent period in socially housed bonnet macaques (Macaca radiata). Dev Psychobiol 55:316-22
Freeman, Willard M; Vanguilder, Heather D; Guidone, Elizabeth et al. (2011) Plasma proteomic alterations in non-human primates and humans after chronic alcohol self-administration. Int J Neuropsychopharmacol 14:899-911
Lyn, Heidi; Pierre, Peter; Bennett, Allyson J et al. (2011) Planum temporale grey matter asymmetries in chimpanzees (Pan troglodytes), vervet (Chlorocebus aethiops sabaeus), rhesus (Macaca mulatta) and bonnet (Macaca radiata) monkeys. Neuropsychologia 49:2004-12
Graef, John D; Godwin, Dwayne W (2010) Intrinsic plasticity in acquired epilepsy: too much of a good thing? Neuroscientist 16:487-95
Acosta, Glen; Hasenkamp, Wendy; Daunais, James B et al. (2010) Ethanol self-administration modulation of NMDA receptor subunit and related synaptic protein mRNA expression in prefrontal cortical fields in cynomolgus monkeys. Brain Res 1318:144-54
Freeman, Willard M; Salzberg, Anna C; Gonzales, Steven W et al. (2010) Classification of alcohol abuse by plasma protein biomarkers. Biol Psychiatry 68:219-22
Cheng, Heng-Jie; Grant, Kathleen A; Han, Qing-Hua et al. (2010) Up-regulation and functional effect of cardiac ?3-adrenoreceptors in alcoholic monkeys. Alcohol Clin Exp Res 34:1171-81
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
McCauley, Anita K; Frank, Steven T; Godwin, Dwayne W (2009) Brainstem nitrergic innervation of the mouse visual thalamus. Brain Res 1278:34-49

Showing the most recent 10 out of 13 publications