黑料网

Abstract

A mong the brain areas affected by acute and chronic administration of alcohol is the ventral tegmental area (VTA). Salience related to reward and reinforcement in alcohol addiction is dictated by the functioning of dopaminergic (DAergic) neurons of the VTA. Acute alcohol increases the rate of spontaneous action potential generation of VTA DAergic neurons in vivo and in vitro . Chronic alcohol has been shown to alter the effects of gamma-aminobutyric acid (GABA) in a number of brain areas. Repeated ethanol administration to mice produces a decreased sensitivity of DAergic VTA neurons to GABA, as measured in extracellular recordings from brain slices; it has been observed that hyposensitivity to GABA induced by chronic alcohol exposure in a number of animal models employing different ethanol treatment regimens. One mechanism by which alcohol could induce this GABAergic hyposensitivity is alteration of the enzyme histone deacetylase (HDAC), which in turn could change the acetylation of histone proteins, which would alter the expression of GABA receptors. It was investigated how HDAC inhibitors affect GABAergic sensitivity of DA VTA neurons after chronic alcohol exposure, and also examined changes in HDAC2 and histone H3-K9 acetylation in the VTA during alcohol withdrawal. Mice were treated with either ethanol (3.5 g/kg, i.p.) or saline twice daily for 3 weeks, and recordings were made at least 14 h after the last injection. In recordings from DA VTA neurons from ethanol-withdrawn mice, sensitivity to GABA (50-500 μM) was reduced. In DA VTA neurons from ethanol-withdrawn mice that were incubated with the HDAC inhibitor SAHA (vorinostat) or trichostatin A (TSA) for two hours, the hyposensitivity of DA VTA neurons to GABA was significantly attenuated. TSA or SAHA treatment did not affect sensitivity to GABA of DA VTA neurons from saline-treated mice. Withdrawal from repeated ethanol was associated with an increase in HDAC2 and a decrease in acetylated H3-K9. Similar findings were observed when we studied the effect of a chronic ethanol-containing diet on GABA sensitivity in the VTA of Sprague-Dawley rats. Significant GABA hyposensitivity was observed in DAergic VTA neurons from rats given access to ethanol-containing diet for two weeks. This GABA hyposensitivity was accompanied by an increase in HDAC2 and a decrease in acetylated H3-K9 in the VTA, and the GABA hyposensitivity was reversed by an acute incubation with SAHA. Therefore, the blockade of HDAC2 by HDAC inhibitors normalizes GABA hyposensitivity of DAergic neurons during withdrawal from chronic ethanol in different paradigms, suggesting that HDAC inhibition can reverse alcohol-induced changes in reward circuitry induced by ethanol exposure

Biography

Mark S Brodie completed his PhD from the University of Illinois at Chicago in the Department of Pharmacology and postdoctoral studies with Thomas Dunwiddie at the University of Colorado Health Sciences Center, where he and Dr. Dunwiddie developed a brain slice preparation of the ventral tegmental area. He is currently a Professor of Physiology and Biophysics, in the College of Medicine of the University of Illinois at Chicago. In addition to being an award-winning teacher, he has actively studied the effects of alcohol on brain reward neurons of the ventral tegmental area for almost 30 years. His work has been fundamental in examining the direct actions of alcohol on neurons of the ventral tegmental area, and in exploring the effects of chronic alcohol on the responses of those neurons to acutely administered alcohol and neurotransmitters.