Ethanol dually modulates GABAergic synaptic transmission onto dopaminergic neurons in ventral tegmental area: Role of μ-opioid receptors

Abstract

The mesolimbic dopaminergic system, originating from the ventral tegmental area (VTA) is implicated in the rewarding properties of ethanol. VTA dopaminergic neurons are under the tonic control of GABAergic innervations. Application of GABAergic agents changes ethanol consumption. However, it is unclear how acute ethanol modulates GABAergic inputs to dopaminergic neurons in the VTA. This report describes ethanol at clinically relevant concentrations (10-40 mM) dually modulates inhibitory postsynaptic currents (IPSCs). IPSCs were mediated by GABA A receptors and were recorded from VTA dopaminergic neurons in acute midbrain slices of rats. Acute application of ethanol reduced the amplitude and increased the paired pulse ratio of evoked IPSCs. Ethanol lowered the frequency but not the amplitude of spontaneous IPSCs. Nevertheless, ethanol had no effect on miniature IPSCs recorded in the presence of tetrodotoxin. These data indicate that ethanol inhibits GABAergic synaptic transmission to dopaminergic neurons by presynaptic mechanisms, and that ethanol inhibition depends on the firing of GABAergic neurons. Application of CGP 52432, a GABA B receptor antagonist did not change ethanol inhibition of IPSCs. Tyr-DAla-Gly-N-Me-Phe-Gly-ol enkephalin (DAMGO), a µ-opioid receptor agonist, conversely, silenced VTA GABAergic neurons and inhibited IPSCs. Of note, in the presence of saturating concentration of DAMGO (3 µM), ethanol potentiated the remaining IPSCs. Thus, ethanol dually modulates GABAergic transmission to dopaminergic neurons in the VTA. Ethanol modulation depends on the activity of VTA GABAergic neurons, which were inhibited by the activation of µ-opioid receptors. This dual modulation of GABAergic transmission by ethanol may be an important mechanism underlying alcohol addiction.

Effects of acute alcohol ingestion on eye movements and cognition: A double-blind, placebo-controlled study

“…In addition, the reduction in the levels of this recept in the brain of alcoholic individuals supports the hypothesis that the interaction between alcohol and GABA is implicated in a dysfunction in the CNS [13–14]. This neurotransmitter is found in different structures involved in visual information processing, such as the ganglion and bipolar retinal cells, the lateral geniculate nucleus (LGN), superior colliculus (SC) and the visual cortex, which are structures that are involved in visual information processing [11–12]. GABA is also involved in the control of ocular movement, the speed which a monkey performs eye movement can be increased or decreased by injection into SC of GABA agonists or antagonists, respectively [15–16].…”

“…The alcohol works as a depressor of the CNS [7, 12], which may alter diffusely cognitive and perceptual processes [2, 6, 18]. Therefore, the present study examined the effects of moderate acute alcohol ingestion (0.08% BAC) on the eye movement pattern, as an indicator of cognitive processing [34].…”

“…One of the examples of evidence that supports this hypothesis shows that the administration of GABA activity enhancers is an efficient method of ceasing alcohol ingestion [12]. In addition, the reduction in the levels of this recept in the brain of alcoholic individuals supports the hypothesis that the interaction between alcohol and GABA is implicated in a dysfunction in the CNS [13–14].…”

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

“…For example, ethanol can hyperpolarize the GABA-containing neurons of the VTA (Gallegos et al, 1999;Xiao and Ye, 2008) and can influence NMDA receptor-mediated excitation of VTA DA neurons (Stobbs et al, 2004). Chronic ethanol is likely to affect various ethanol-sensitive properties differently, resulting in apparent increases or decreases in the effects of ethanol.…”

Modulation of ethanol reward sensitivity by nicotinic acetylcholine receptors containing the α6 subunit

“…Nicotine activates VTA-DAergic neurons directly by binding to and activating nicotinic acetylcholine receptors (nAChRs), pentameric ligand-gated cation channels normally activated by the endogenous neurotransmitter, acetylcholine (ACh). In contrast, the mechanism by which alcohol activates these same neurons is complex and likely involves multiple neurotransmitter systems (Liu, Hendrickson, et al, 2013; Liu, Zhao-Shea, McIntosh, Gardner, & Tapper, 2012; Morikawa & Morrisett, 2010; Pidoplichko, DeBiasi, Williams, & Dani, 1997; Theile, Morikawa, Gonzales, & Morrisett, 2011; Xiao & Ye, 2008). …”