Ethanol Suppression of Ventral Tegmental Area GABA Neuron Electrical Transmission Involves N-Methyl-d-aspartate Receptors

Abstract

Ventral tegmental area (VTA) GABA neurons are critical substrates modulating the mesocorticolimbic dopamine system implicated in natural and drug reward. The aim of this study was to evaluate the effects of ethanol on glutamatergic and GABAergic modulation of VTA GABA neuron electrical synaptic transmission. We evaluated the effects of systemic ethanol (0.05-2.0 g/kg i.p.), the N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801; 0.05-0.2 mg/kg i.v.), the connexin-36 gap junction blocker quinidine (5-20 mg/kg i.v.), the fast-acting barbiturate methohexital (Brevital; 5-10 mg/kg i.v.), and the benzodiazepine chlordiazepoxide (Librium; 5-10 mg/kg i.v.), as well as in situ VTA administration of NMDA and the GABA A receptor agonist muscimol, on VTA GABA neuron spontaneous activity and internal capsule stimulus-induced poststimulus spike discharges (ICPSDs). Systemic ethanol, quinidine, and dizocilpine reduced, whereas local NMDA enhanced, and the systemic and local GABA A receptor modulators did not significantly alter VTA GABA neuron ICPSDs. Ethanol potentiated dizocilpine inhibition of VTA GABA neuron ICPSDs, but not quinidine inhibition. In situ microelectrophoretic application of dopamine markedly enhanced VTA GABA neuron firing rate (131%), spike duration (124%), and spike coupling, which were blocked by systemic quinidine. These findings indicate that VTA GABA neurons are coupled electrically via gap junctions and that the inhibitory effect of ethanol on electrical transmission is primarily via inhibition of NMDA receptor-mediated excitation, not via enhancement of GABA receptor-mediated inhibition. Thus, the rewarding properties of ethanol may result from inhibitory effects on excitatory glutamatergic neurotransmission between electrically coupled networks of midbrain GABA neurons.The two major types of membrane-bound proteins that are directly affected by physiologically relevant levels of ethanol (i.e., concentrations up to 100 mM or 460 mg/dl, at which point ethanol can be lethal in humans) are ligand-gated ion channels and voltage-dependent calcium channels (Harris, 1999). Ligand-gated ion channels, including ␥-GABA, N-methyl-D-aspartate (NMDA), glycine, nicotinic cholinergic, and 5-hydroxytryptamine type 3 receptors play a major role in synaptic transmission and have been shown to be directly modulated by ethanol. In particular, the intoxicating and rewarding properties of ethanol seem to result from either attenuation of NMDA receptor-mediated and/or enhancement of GABA receptor-mediated neurotransmission (for reviews, see Chester and Cunningham, 2002;Davies, 2003).The ventral tegmental area (VTA) is the neuronal origin of the mesocorticolimbic dopamine projection and has been implicated in locomotor activity, cognition, and in the reinforcing/rewarding properties of drugs of abuse (Wise, 1996), including ethanol. With drugs such as cocaine and amphetamine, the link to dopamine systems is readily apparent; however, with other drugs such as opiates and ethanol, the link to dopamin...

The role of GABAA receptors in the development of alcoholism

“…It has been shown that VTA GABA neurons are coupled electrically via gap junctions (Stobbs et al, 2004). The predominant GABA A receptors expressed in the VTA are α 2 , α 3 , α 4 , β 1 , β 3 , and γ 2 (Okada et al, 2004).…”

“…The predominant GABA A receptors expressed in the VTA are α 2 , α 3 , α 4 , β 1 , β 3 , and γ 2 (Okada et al, 2004). In rats, acute ethanol exposure (20-80mM) excites DA neurons directly but also indirectly by reducing the firing rate of VTA GABAergic neurons (Gallegos et al, 1999;Xiao et al, 2007) and by influencing NMDA receptor-mediated excitation (Stobbs et al, 2004). Chronic exposure to ethanol enhances baseline activity of GABA neurons and induces tolerance to ethanol inhibition of the firing rate (Gallegos et al, 1999).…”

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

“…Likewise, Maldve et al (2004) found ethanol inhibition of vesicular release at excitatory synapses and Brancucci et al (2004) found that ethanol reduced the efficacy of excitatory glutamatergic transmission on dopaminergic neurons in the substantia nigra pars compacta. In the ventral tegmental area, Stobbs et al (2004) found that ethanol had inhibitory effects on excitatory glutamatergic neurotransmission. Additionally, ethanol is reported to diminish glutamate release in nucleus accumbens (Piepponen et al, 2002;Yan et al, 1998), to reduce the probability of glutamate release at the crayfish neuromuscular junction (Strawn and Cooper, 2002), and to minimize potassium stimulated glutamate release in the guinea pig hippocampus (Butters et al, 2001).…”

Drunken Membranes: Short-Chain Alcohols Alter Fusion of Liposomes to Planar Lipid Bilayers

“…But despite decades of investigation, the evidence is inconclusive for any specific molecular target for ethanol on any protein (for reviews see (6,7)). Many potential protein targets have been identified (4,8) including voltage-gated Na þ channels (9), adenylyl cyclase (10,11), guanine nucleotide binding protein G s (12), the GLT1 glutamate transporter (13), gap junctions (14), g-aminobutyric acid (GABA) A receptors (6), n-methyl-daspartate (NMDA) receptors (15), nicotinic acetylcholine receptor (nAChR) channels (16,17), and the cannabinoid receptor 1 (18). One system within the brain that appears to be sensitive to alcohol dependence is the endocannabinoid system (for review see (19)).…”