Reversal of Alcohol-Induced Dysregulation in Dopamine Network Dynamics May Rescue Maladaptive Decision-making.
UNLABELLED
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.


SIGNIFICANCE STATEMENT
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.
['Schindler|Abigail G|AG|', 'Soden|Marta E|ME|', 'Zweifel|Larry S|LS|', 'Clark|Jeremy J|JJ|http://orcid.org/0000-0002-8885-0020']
D020268:Alcohol-Induced Disorders, Nervous System D000818:Animals D000831:Animals, Newborn D002492:Central Nervous System Depressants D003657:Decision Making D004195:Disease Models, Animal D004298:Dopamine D059290:Dopaminergic Neurons D004558:Electric Stimulation D000431:Ethanol D066298:In Vitro Techniques D053444:Inhibitory Postsynaptic Potentials D008297:Male D017551:Microdialysis D009434:Neural Pathways D018408:Patch-Clamp Techniques D051381:Rats D017207:Rats, Sprague-Dawley D012309:Risk-Taking D017557:Ventral Tegmental Area
dopamine decision-making alcohol adolescent therapeutic GABA