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-Aα1 receptor (GABA (A-α1) 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 In recordings from pDAergic VTA neurons in brain slices from ethanol-withdrawn mice, sensitivity to GABA (50-500 μM) was reduced. In brain slices from ethanol-withdrawn mice incubated with the HDACi SAHA (vorinostat) or trichostatin A (TSA) for 2 h, the hyposensitivity of pDAergic VTA neurons to GABA was significantly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-α1) 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.
Highlights
The mesolimbic dopamine (DA) system projects from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), prefrontal cortex, basolateral amygdala, and to other corticolimbic structures (Albanese and Minciacchi, 1983; Oades and Halliday, 1987)
For slices treated with DMSO or histone deacetylases (HDACs) inhibitors (HDACi), recordings were made in up to eight neurons per slice, with an average number of cells per slice of 4.9±0.42
There was a significant difference in the baseline frequency of firing rate of pDAergic VTA neurons among these groups, with Tukey’s mean comparison indicating a significant difference between only the ethanol injected, DMSO-treated (E-DMSO) cells and the ethanol-injected, trichostatin A (TSA)-treated (E-TSA) cells (Tukey’s post hoc test, po0.05 for E-DMSO and E-TSA groups, p40.05 for comparisons of all other groups) (Table 1)
Summary
The mesolimbic dopamine (DA) system projects from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), prefrontal cortex, basolateral amygdala, and to other corticolimbic structures (Albanese and Minciacchi, 1983; Oades and Halliday, 1987). Modifications in chromatin architecture could underlie the long-lasting changes in neuronal gene expression and synaptic plasticity, and these changes could explain the processes involved in addictive behaviors (Renthal and Nestler, 2009a; Moonat et al, 2010). Recent studies have shown that when cocaine is administered at doses necessary to produce locomotor sensitization and conditioned place preference, histone hyperacetylation at specific brain areas relevant to the development of addictive behavior was observed (Kumar et al, 2005; Levine et al, 2005; Renthal and Nestler, 2008). Higher HDAC2 expression-induced deficits in histone H3-K9 acetylation and associated synaptic plasticity in the amygdala has been shown to be involved in alcoholdrinking behaviors (Moonat et al, 2013). We investigated the effects of alcohol treatment and withdrawal on the levels of HDAC2, histone acetylation, and GABA-A a1 receptor (GABA (A-a1) R) subunit in the VTA of mice
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