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

• Published in: Neuron (Cambridge, Mass.) Mass.), 2016-10, Vol.92 (2), p.493-504
• Main Authors: Ostroumov, Alexey, Thomas, Alyse M., Kimmey, Blake A., Karsch, Jordan S., Doyon, William M., Dani, John A.
• Format: Article
• Language: English
• Subjects: Acetazolamide - pharmacology; Alcohol use; alcohol use disorder; Alcoholism - metabolism; Alcoholism - psychology; Animals; Carbonic Anhydrase Inhibitors - pharmacology; Central Nervous System Depressants - administration & dosage; chloride gradient; Conditioning, Operant; Dopamine - metabolism; Dopaminergic Neurons - metabolism; Ethanol - administration & dosage; Experiments; GABA; gamma-Aminobutyric Acid - metabolism; Hormone Antagonists - pharmacology; HPA axis; K Cl- Cotransporters; KCC2; Male; mesolimbic; Microdialysis; Mifepristone - pharmacology; neuroendocrine; Neurons; nucleus accumbens; Patch-Clamp Techniques; Rats; Rats, Long-Evans; Receptors, GABA-A - metabolism; reward; Rodents; Self Administration; Stress, Psychological - metabolism; Symporters - drug effects; Symporters - metabolism; Ventral Tegmental Area - metabolism
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2016.09.029

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 GABAA 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. •Stress increases alcohol self-administration•Stress attenuates alcohol-induced dopamine signals•Stress alters mesolimbic circuit inhibition, shifting GABA toward excitation•Stress hormones impair the Cl- extrusion capacity of the transporter KCC2 Ostroumov et al. show that stress exposure attenuates alcohol-induced dopamine signals and increases alcohol self-administration in rodents. Stress causes midbrain circuitry changes via neuroendocrine signals that ultimately impair a chloride transporter and shift specific GABA inhibition toward excitation.