Stress Increases Ethanol Self-Administration via a Shift toward Excitatory GABA Signaling in the Ventral Tegmental...

Stress is a well-known risk factor for subsequent alcohol abuse, but the neural mechanisms underlying interactions between stress and alcohol remain largely unknown. Addictive drug reinforcement and stress signaling involve common neural circuitry, including the mesolimbic dopamine system. We demonstrate in rodents that pre-exposure to stress attenuates alcohol-induced dopamine responses and increases alcohol self-administration. The blunted dopamine signaling resulted from ethanol-induced excitation of GABA neurons in the ventral tegmental area. Excitation of GABA neurons was mediated by GABA_A receptor activation and involved stress-induced functional downregulation of the K⁺, Cl^- cotransporter, KCC2. Blocking stress hormone receptors, enhancing KCC2 function, or preventing excitatory GABA signaling by alternative methods all prevented the attenuated alcohol-induced dopamine response and prevented the increased alcohol self-administration. These results demonstrate that stress alters the neural and behavioral responses to alcohol through a neuroendocrine signal that shifts inhibitory GABA transmission toward excitation.