Contingent and non-contingent effects of low-dose ethanol on GABA neuron activity in the ventral tegmental area

Abstract

Ventral tegmental area (VTA) GABA neurons appear to be critical regulators of mesocorticolimbic dopamine (DA) neurotransmission, which has been implicated in alcohol reward. The aim of this study was to evaluate the effects of low-dose "non-contingent" intravenous (IV) ethanol (0.01-0.1 g/kg) on VTA GABA neuron firing rate and synaptic responses, as well as VTA GABA neuron firing rate during low-dose "contingent" IV ethanol selfadministration. Intravenous administration of 0.01-0.03 g/kg ethanol significantly increased VTA GABA neuron firing rate and afferent-evoked synaptic responses. In the runway selfadministration paradigm, presentation of an olfactory cue (S+; almond extract) or no-cue (S−; no odor) in the Start box was paired with IV administration of low-dose ethanol (0.01 g/kg) or saline in the Target box. Runway excursion times decreased significantly in association during S+, and increased significantly during S− conditions. The firing rate of VTA GABA neurons markedly increased when rats received 0.01 g/kg IV ethanol in the Target box. VTA GABA neuron firing increased in the Start box of the runway in association with S+, but not S−. These findings demonstrate that VTA GABA neurons are activated by low-dose IV ethanol and that their firing rate increases in anticipation of ethanol reward.

Novel Therapeutic Strategies for Alcohol and Drug Addiction: Focus on GABA, Ion Channels and Transcranial Magnetic Stimulation

“…In addition, a subset of VTA GABA receptors may be implicated in the development of addictive behavior. In particular, it has been reported that activation of central GABAergic neurotransmission (particularly through GABA B receptors of the VTA) is closely connected with mesolimbic dopaminergic neurotransmission during rewarding processes (Diana et al, 2003;Fadda et al, 2003;Steffensen et al, 2009).…”

“…Acute exposure to ethanol potentiates GABA A receptor function by complex effects on pre-and postsynaptic elements of GABAergic synapses (Fleming et al, 2009) and accordingly, induces a CNS depression secondary to enhanced inhibitory transmission. On the other hand, chronic ethanol exposure seems to induce compensatory adaptations to the acute facilitatory effects of ethanol on GABAergic synapses (Steffensen et al, 2009;Diana et al, 2003), such as marked changes in the expression of specific GABA A receptor subunits and alterations in the subunit composition of these receptors, which are primarily responsible for alterations in GABAergic signalling associated with chronic ethanol exposure (Weiner and Valenzuela, 2006). These adaptive changes are thought to lead to a pronounced hypofunction of GABAergic neurotransmission and possibly the development of tolerance to the effects of ethanol on these synapses (Weiner and Valenzuela, 2006).…”

Alcohol use disorders and current pharmacological therapies: the role of GABAA receptors

“…Social drinking can produce a low-to-moderate concentration of EtOH (≤30 mmol/L) in the brain. Animal studies have shown that a low dose of EtOH (0.01 g/kg, <10 mmol/L) applied to VTA could significantly increase GABA neuron firing rate and afferent-evoked synaptic responses [73] . Voluntary…”

“…In addition, a subset of VTA GABA A Rs is implicated in the development of addictive behavior. In particular, the activation of central GABAergic neurotransmission is linked to mesolimbic dopaminergic neurotransmission during rewarding processes [73,100,105] . We suggest that preclinical and clinical studies should place more emphasis on the GABAergic system as a pharmacotherapeutic target for the treatment of AUD.…”

Full-Gestational Exposure to Nicotine and Ethanol Results in Long-Term Dysregulation in the Ventral Tegmental Area

“…Studies using anesthetized rats demonstrated that low dose ethanol (0.01-0.03 g/kg) increases VTA GABA firing (Steffensen et al 2009), whereas higher doses of ethanol (0.2-2.0 g/kg) demonstrate an inhibition of GABAergic activity (Gallegos et al 1999). An electrophysiological study examined modulation of VTA DA neurons after chronic exposure to ethanol in C57BL/6J mice.…”