title: Stress Increases Ethanol Self-Administration via a Shift toward Excitatory GABA Signaling in the Ventral Tegmental Area.
abstract: 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 GABAAreceptor 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.
authors.affiliation: Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Alexey
authors.initials: A
authors.lastname: Ostroumov
authors.affiliation: Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Alyse M
authors.initials: AM
authors.lastname: Thomas
authors.affiliation: Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Blake A
authors.initials: BA
authors.lastname: Kimmey
authors.affiliation: Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Karsch
authors.affiliation: Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Doyon
authors.affiliation: Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: johndani@upenn.edu.
authors.forename: John A
authors.initials: JA
authors.lastname: Dani
mesh_terms: D000086:Acetazolamide / Q000494:pharmacology; D000437:Alcoholism / Q000378:metabolism* / Q000523:psychology; D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000008:administration & dosage*; D003216:Conditioning, Operant; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000378:metabolism*; D000431:Ethanol / Q000008:administration & dosage*; D006727:Hormone Antagonists / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D015735:Mifepristone / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D051381:Rats; D020318:Rats, Long-Evans; D011963:Receptors, GABA-A / Q000378:metabolism; D012646:Self Administration; D013315:Stress, Psychological / Q000378:metabolism*; D027981:Symporters / Q000187:drug effects / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*; D000096922:K Cl- Cotransporters
chemical_list: D000086:Acetazolamide; D002257:Carbonic Anhydrase Inhibitors; D002492:Central Nervous System Depressants; D004298:Dopamine; D000431:Ethanol; D006727:Hormone Antagonists; D015735:Mifepristone; D011963:Receptors, GABA-A; D027981:Symporters; D005680:gamma-Aminobutyric Acid; D000096922:K Cl- Cotransporters
keywords: GABA; HPA axis; KCC2; alcohol use disorder; chloride gradient; mesolimbic; microdialysis; neuroendocrine; nucleus accumbens; reward