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

Abstract

Putative dopaminergic (pDAergic) ventral tegmental area (VTA) neurons have 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 pDAergic 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 pDAergic VTA neurons by HDAC inhibitors (HDACi), and also measured the levels of HDAC2, histone (H3-K9) acetylation, and GABA-Aa1 receptor (GABA (A-a1) R) subunit in VTA during ethanol withdrawal. Mice were injected intraperitoneally (ip) with either ethanol (3.5 g/kg) or saline twice daily for 3 weeks. In recordings from pDAergic VTA neurons in brain slices from ethanol-withdrawn mice, sensitivity to GABA (50-500 mM) was reduced. In brain slices from ethanol-withdrawn mice incubated with the HDACi SAHA (vorinostat) or trichostatin A (TSA) for 2 h, the hyposensitivity of pDAergic VTA neurons to GABA was significantly attenuated. There was no effect of TSA or SAHA on GABA sensitivity of pDAergic 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-a1) R subunits in the VTA. Therefore, blockade of upregulation of HDAC2 by HDACi 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.

Histone-Mediated Epigenetics in Addiction

“…One of many examples of this is with Trichostatin A (TSA), a general HDAC inhibitor with antitumor activity (Drummond et al, 2005), that has been shown to decrease the motivation for and intake of addictive drugs (Romieu et al, 2008). Such a finding has been observed with other HDAC inhibitors and variations to the time and route of drug administration (Arora et al, 2013; Kim et al, 2014; Raybuck et al, 2013). …”

Effects of histone deacetylase inhibitors on amygdaloid histone acetylation and neuropeptide Y expression: a role in anxiety-like and alcohol-drinking behaviours

“…Recently, the acetylation state of histones has emerged as a potential epigenetic mechanism in coordinating the effects of alcohol in the brain as well as related behaviors (Wang et al, 2007; Pandey et al, 2008; Pascual et al, 2012; Sakharkar et al, 2012; Arora et al, 2013; Moonat et al, 2013; Warnault et al, 2013). We recently reported that innately higher levels of HDAC2 in the CeA and MeA of P rats was reciprocally correlated with deficits in histone H3 acetylation levels of synaptic plasticity-related genes, e.g.…”

Histone Deacetylase Inhibition Rescues Maternal Deprivation-Induced GABAergic Metaplasticity through Restoration of AKAP Signaling

“…Chromatin modifications by enzymes such as histone deacetylases (HDACs) also alter gene expression in neurons and neuroplasticity underlying memory formation (Abel and Zukin, 2008;Haggarty and Tsai, 2011). GABA A receptors (GABA A R) are epigenetically regulated in response to early-life stress and addictive drugs (Arora et al, 2013;Kennedy et al, 2013). GABA A R signaling in DA neurons plays a key role in reward-motivated learning (Laviolette and van der Kooy, 2001;Parker et al, 2011).…”