Tonic GABAergic inhibition, via GABAA receptors containing αβƐ subunits, regulates excitability of ventral tegmental area dopamine neurons

Abstract

The activity of midbrain dopamine neurons is strongly regulated by fast synaptic inhibitory γ-Aminobutyric acid (GABA)ergic inputs. There is growing evidence in other brain regions that low concentrations of ambient GABA can persistently activate certain subtypes of GABAA receptor to generate a tonic current. However, evidence for a tonic GABAergic current in midbrain dopamine neurons is limited. To address this, we conducted whole-cell recordings from ventral tegmental area (VTA) dopamine neurons in brain slices from mice. We found that application of GABAA receptor antagonists decreased the holding current, indicating the presence of a tonic GABAergic input. Global increases in GABA release, induced by either a nitric oxide donor or inhibition of GABA uptake, further increased this tonic current. Importantly, prolonged inhibition of the firing activity of local GABAergic neurons abolished the tonic current. A combination of pharmacology and immunohistochemistry experiments suggested that, unlike common examples of tonic inhibition, this current may be mediated by a relatively unusual combination of α4βƐ subunits. Lastly, we found that the tonic current reduced excitability in dopamine neurons suggesting a subtractive effect on firing activity.