title: Reversal of Alcohol-Induced Dysregulation in Dopamine Network Dynamics May Rescue Maladaptive Decision-making.
abstract: Alcohol is the most commonly abused substance among adolescents, promoting the development of substance use disorders and compromised decision-making in adulthood. We have previously demonstrated, with a preclinical model in rodents, that adolescent alcohol use results in adult risk-taking behavior that positively correlates with phasic dopamine transmission in response to risky options, but the underlying mechanisms remain unknown. Here, we show that adolescent alcohol use may produce maladaptive decision-making through a disruption in dopamine network dynamics via increased GABAergic transmission within the ventral tegmental area (VTA). Indeed, we find that increased phasic dopamine signaling after adolescent alcohol use is attributable to a midbrain circuit, including the input from the pedunculopontine tegmentum to the VTA. Moreover, we demonstrate that VTA dopamine neurons from adult rats exhibit enhanced IPSCs after adolescent alcohol exposure corresponding to decreased basal dopamine levels in adulthood that negatively correlate with risk-taking. Building on these findings, we develop a model where increased inhibitory tone on dopamine neurons leads to a persistent decrease in tonic dopamine levels and results in a potentiation of stimulus-evoked phasic dopamine release that may drive risky choice behavior. Based on this model, we take a pharmacological approach to the reversal of risk-taking behavior through normalization of this pattern in dopamine transmission. These results isolate the underlying circuitry involved in alcohol-induced maladaptive decision-making and identify a novel therapeutic target.
  
  
  CONCLUSIONS
  One of the primary problems resulting from chronic alcohol use is persistent, maladaptive decision-making that is associated with ongoing addiction vulnerability and relapse. Indeed, studies with the Iowa Gambling Task, a standard measure of risk-based decision-making, have reliably shown that alcohol-dependent individuals make riskier, more maladaptive choices than nondependent individuals, even after periods of prolonged abstinence. Using a preclinical model, in the current work, we identify a selective disruption in dopamine network dynamics that may promote maladaptive decision-making after chronic adolescent alcohol use and demonstrate its pharmacological reversal in adulthood. Together, these results highlight a novel neural mechanism underlying heightened risk-taking behavior in alcohol-dependent individuals and provide a potential therapeutic target for further investigation.
authors.affiliation: Departments of Psychiatry and Behavioral Sciences and.
authors.forename: Abigail G
authors.initials: AG
authors.lastname: Schindler
authors.affiliation: Departments of Psychiatry and Behavioral Sciences and Pharmacology, University of Washington, Seattle, Washington 98195.
authors.forename: Marta E
authors.initials: ME
authors.lastname: Soden
authors.affiliation: Departments of Psychiatry and Behavioral Sciences and Pharmacology, University of Washington, Seattle, Washington 98195.
authors.forename: Larry S
authors.initials: LS
authors.lastname: Zweifel
authors.affiliation: Departments of Psychiatry and Behavioral Sciences and jjc1@uwashington.edu.
authors.forename: Jeremy J
authors.identifier: http://orcid.org/0000-0002-8885-0020
authors.initials: JJ
authors.lastname: Clark
mesh_terms: D020268:Alcohol-Induced Disorders, Nervous System / Q000150:complications*; D000818:Animals; D000831:Animals, Newborn; D002492:Central Nervous System Depressants / Q000633:toxicity*; D003657:Decision Making / Q000187:drug effects*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000187:drug effects*; D004558:Electric Stimulation; D000431:Ethanol / Q000633:toxicity*; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008297:Male; D017551:Microdialysis; D009434:Neural Pathways / Q000187:drug effects; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D012309:Risk-Taking; D017557:Ventral Tegmental Area / Q000473:pathology
chemical_list: D002492:Central Nervous System Depressants; D000431:Ethanol; D004298:Dopamine
keywords: GABA; adolescent; alcohol; decision-making; dopamine; therapeutic