Hyposensitivity to Gamma-aminobutyric Acid in the Ventral Tegmental Area during Alcohol Withdrawal: Reversal by Histone Deacetylase Inhibitors

Putative dopaminergic (pDAergic) ventral tegmental area (VTA) neurons play an important role in alcohol addiction. Acute ethanol increases the activity of pDAergic neurons, and withdrawal from repeated ethanol administration produces a decreased sensitivity of pDA VTA neurons to GABA. Recent studies show that behavioral changes induced by chronic alcohol are reversed by inhibitors of histone deacetylases (HDACs). Whether HDAC-induced histone modifications regulate changes in GABA sensitivity of VTA pDAergic neurons during withdrawal is unknown. Here, we investigated modulation of withdrawal-induced changes in GABA sensitivity of pDA VTA neurons by HDAC inhibitors and also measured the levels of HDAC2, histone (H3-K9) acetylation, and GABA-A􀄮1 receptor subunit in VTA during ethanol withdrawal. Mice were injected intraperitoneally with either ethanol (3.5 g/kg) or saline twice daily for 3 weeks. In recordings from pDA VTA neurons in brain slices from ethanol-withdrawn mice, sensitivity to GABA (50 – 500 μM) was reduced. In brain slices from ethanol-withdrawn mice incubated with the HDAC inhibitor SAHA (vorinostat) or trichostatin A (TSA) for two hours, the hyposensitivity of pDA VTA neurons to GABA was significantly attenuated. There was no effect of TSA or SAHA on GABA sensitivity of pDA VTA neurons from saline-treated mice. In addition, ethanol withdrawal was associated with an increase in levels of HDAC2 and a decrease in histone (H3-K9) acetylation and levels of GABA (A- 􀄮1) R subunits in the VTA. Therefore, blockade of upregulation of HDAC2 by HDAC inhibitors normalizes GABA hyposensitivity of pDAergic neurons developed during withdrawal after chronic ethanol treatment, which suggests the possibility that inhibition of HDACs can reverse ethanol-induced neuroadaptational changes in reward circuitry.