BDNF restores impaired long-term potentiation of GABAergic synapses induced by chronic ethanol exposure in the VTA and attenuates reward-seeking behavior

Cellular and synaptic plasticity in ventral tegmental area (VTA) play a key role in alcohol use disorder (AUD). Here, we first delineated the in vivo dynamics of dopamine (DA) neuron activity in VTA during chronic intermittent ethanol exposure: initial sensitization was followed by a phase of attenuated and dysregulated response upon the first high-concentration exposure, culminating in stable hyper-responsiveness. Chronic ethanol exposure impaired long-term potentiation of GABAergic synapses (LTP_GABA) on VTA DA neurons by reducing presynaptic GABA release, and induced lower levels of brain-derived neurotrophic factor (BDNF) expression in VTA. The impaired LTP_GABA recovered after 7 days of withdrawal, in parallel with a restoration of BDNF expression in the VTA. Using a combination of pharmacological and region-specific genetic knockdown approaches, we demonstrate that BDNF signaling through its receptor TrkB is both necessary and sufficient for LTP_GABA induction. Crucially, in VTA slices from chronic ethanol-exposed mice, BDNF application rescued the impaired LTP_GABA. In vivo, microinjection of BDNF into the VTA rapidly restored the hyperactive state of DA neuron activity induced by ethanol consumption (6 mice per group), an effect that was mimicked by the GABA_A receptor agonist muscimol and blocked by co-administration of either the TrkB antagonist K252a or the GABA_A receptor antagonist Gabazine. Furthermore, BDNF microinjection significantly attenuated cue-driven ethanol-seeking behavior (reducing the progressive ratio breakpoint by 52%; 6 mice per group), an effect depending on TrkB activation. Together, our findings reveal that chronic ethanol exposure impairs GABAergic plasticity via BDNF-TrkB signaling, while BDNF restores the impaired LTP_GABA and dynamics of DA neuron activity, and attenuates ethanol seeking, identifying a novel therapeutic target for AUD.