Abstract
The neural mechanisms underlying alcohol dependence are not well-understood. GABAergic neurons in the ventral tegmental area (VTA) are a relevant target for ethanol. They are inhibited by ethanol at physiologically-relevant levels in vivo and display marked hyperexcitability during withdrawal. In the present study, we examined the effects of the GABA(A) receptor agonist muscimol on VTA neurons ex vivo following withdrawal from acute and chronic ethanol exposure. We used standard cell-attached mode electrophysiology in the slice preparation to evaluate the effects of muscimol on VTA GABA neuron firing rate following exposure to acute and chronic ethanol in male CD-1 GAD-67 GFP mice. In the acute condition, the effect of muscimol on VTA neurons was evaluated 24 h and 7 days after a single in vivo dose of saline or ethanol. In the chronic condition, the effect of muscimol on VTA neurons was evaluated 24 h and 7 days after either 2 weeks of twice-daily IP ethanol or saline or following exposure to chronic intermittent ethanol (CIE) vapor or air for 3 weeks. VTA GABA neuron firing rate was more sensitive to muscimol than DA neuron firing rate. VTA GABA neurons, but not DA neurons, were resistant to the inhibitory effects of muscimol recorded 24 h after a single ethanol injection or chronic ethanol exposure. Administration of the NMDA receptor antagonist MK-801 before ethanol injection restored the sensitivity of VTA GABA neurons to muscimol inhibition. Seven days after ethanol exposure, VTA GABA neuron firing rate was again susceptible to muscimol's inhibitory effects in the acute condition, but the resistance persisted in the chronic condition. These findings suggest that VTA GABA neurons exclusively undergo a shift in GABA(A) receptor function following acute and chronic exposure. There appears to be transient GABA(A) receptor-mediated plasticity after a single exposure to ethanol that is mediated by NMDA glutamate receptors. In addition, the resistance to muscimol inhibition in VTA GABA neurons persists in the dependent condition, which may contribute to the the hyperexcitability of VTA GABA neurons and inhibition of VTA DA neurons during withdrawal as well as the motivation to seek alcohol.
Highlights
Alcoholism is a chronic relapsing disorder that has an enormous impact on society
We evaluated the effects of muscimol on ventral tegmental area (VTA) neuron firing rate at concentrations ranging from 0.01 to 10.0 μM
The overall aim of this study was to investigate the electrophysiological components of the mechanism underlying the hyperexcitability of VTA GABA neurons following withdrawal from chronic ethanol
Summary
Alcoholism is a chronic relapsing disorder that has an enormous impact on society. A major goal of research on alcoholism is to characterize the critical neural substrates that are most sensitive to alcohol, adapt in association with chronic consumption and drive subsequent alcohol-seeking behavior. The VTA is highly involved in adaptive reward and motivation processing and is composed of DA (65%), γ-aminobutyric acid (GABA; 30%), and glutamate (GLU; 5%) neurons (Dobi et al, 2010). Both in vivo (Gessa et al, 1985) and in vitro (Brodie et al, 1990; Brodie and Appel, 1998) electrophysiological studies indicate that acute ethanol increases VTA DA neuron firing rate (EC50 of 120 mM in the slice) and DA release in limbic structures (Imperato and Di Chiara, 1986), and that withdrawal from chronic ethanol reduces DA firing rate and release in the NAc (Diana et al, 1993). VTA GABA neurons undergo pronounced adaptation during withdrawal from chronic ethanol
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