GABAergic Neuron Activation in the RMTg-VTA Pathway Modulates Dopaminergic Neuron Excitability and Social Stress Susceptibility in Male Mice.

BACKGROUND: Chronic social stress is a significant risk factor for neuropsychiatric disorders such as anxiety and depression, with the ventral tegmental area (VTA) playing a pivotal role. Although chronic social defeat stress (CSDS) induces adaptations in VTA dopaminergic (DA) neurons, the role of GABAergic modulation in regulating DA neuron excitability and related behaviors remains unclear. METHODS: In this study, we investigated the effects of GABA(A) receptor activation on VTA DA neuron activity and social stress behaviors in a CSDS model. We employed electrophysiological recordings, immunohistochemistry, and optogenetic manipulations to assess changes in DA neuron excitability and GABAergic input from the rostromedial tegmental nucleus (RMTg). RESULTS: Our results show that susceptible mice exhibit enhanced spontaneous firing of VTA DA neurons and increased GABA(A) receptor expression. Pharmacological activation of GABA(A) receptors suppressed DA neuron hyperactivity and reversed social avoidance behavior. Moreover, optogenetic stimulation of RMTg GABAergic projections to the VTA significantly reduced DA neuron firing and mitigated social avoidance in susceptible mice. CONCLUSION: These findings suggest that activation of RMTg GABAergic neurons projecting to VTA effectively reduces DA neuron excitability in the VTA and plays a critical role in the modulation of stress-induced behavioral deficits, offering a potential therapeutic target for neuropsychiatric disorders.