A novel positive modulator of α4-GABAA receptors, XHe-III-74, reduces ethanol intake in mouse “drinking in the dark” model

Elevated levels of dopamine in the nucleus accumbens (nAc) as a consequence of increased activation of dopaminergic neurons in the VTA are associated with the reinforcing properties of ethanol consumption, but whether the initiation of drug-response is connected to a direct activation of dopaminergic cell bodies in the VTA region or involves GABAergic neurons in VTA and/or the nAc is unclear. To this end, neuronal firing rate was recorded simultaneously in the VTA and nAc of awake and freely-moving C57BL6/J mice receiving an intraperitoneal (i.p.) injection of ethanol (0.75, 2.0, or 3.5 g/kg) or saline. Recorded units were classified based on electrophysiological properties and the pharmacological response to the dopamine D2 receptor agonist quinpirole into putative dopaminergic (DA) neurons and fast-spiking or slow-spiking putative GABAergic neurons. Our data show that ethanol acutely decreases the firing frequency of GABAergic units in both the VTA and nAc in a dose-dependent manner, and enhances the firing rate of DA neurons. In order to define the onset of ethanol-induced rate changes normalized population vectors describing the collective firing rate of classes of neurons over time were generated and compared with saline-treatment. Population vectors of DA neurons in the VTA and GABAergic units in the nAc showed a significant deviation from the saline condition within 40 s following ethanol-administration (2.0 g/kg), while inhibition of GABAergic units in the VTA had a slower onset. In conclusion, the data presented here suggests that EtOH exerts a direct effect on DA firing frequency, but that decreased firing frequency of inhibitory neurons in VTA and nAc contributes to the dopamine-elevating properties of ethanol.