title: Triple monoamine uptake inhibitors demonstrate a pharmacologic association between excessive drinking and impulsivity in high-alcohol-preferring (HAP) mice.
abstract: Approximately 30% of current drinkers in the United States drink excessively, and are referred to as problem/hazardous drinkers. These individuals, who may not meet criteria for alcohol abuse or dependence, comprise binge, heavy drinkers, or both. Given their high prevalence, interventions that reduce the risk of binge and heavy drinking have important public health implications. Impulsivity has been repeatedly associated with excessive drinking in the clinical literature. As impulsivity is correlated with, and may play a critical role in, the initiation and maintenance of excessive drinking, this behavior may be an important target for therapeutic intervention. Hence, a better understanding of pharmacological treatments capable of attenuating excessive drinking and impulsivity may markedly improve clinical outcomes. The high-alcohol-preferring (HAP) mice represent a strong rodent model to study the relationship between impulsivity and excessive alcohol drinking, as recent evidence indicates they consume high levels of alcohol throughout their active cycle and are innately impulsive. Using this model, the present study demonstrates that the triple monoamine uptake inhibitors (TUIs) amitifadine and DOV 102, 677 effectively attenuate binge drinking, heavy drinking assessed via a 24-hour free-choice assay, and impulsivity measured by the delay discounting procedure. In contrast, 3-PBC, a GABA-A α1 preferring ligand with mixed agonist-antagonist properties, attenuates excessive drinking without affecting impulsivity. These findings suggest that in HAP mice, monoamine pathways may predominate as a common mechanism underlying impulsivity and excessive drinking, while the GABAergic system may be more salient in regulating excessive drinking. We further propose that TUIs such as amitifadine and DOV 102, 677 may be used to treat the co-occurrence of impulsivity and excessive drinking.
authors.affiliation: Department of Psychology, Indiana University-Purdue University, Indianapolis, IN, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: O'Tousa
authors.forename: Kaitlin T
authors.initials: KT
authors.lastname: Warnock
authors.forename: Liana M
authors.initials: LM
authors.lastname: Matson
authors.forename: Ojas A
authors.initials: OA
authors.lastname: Namjoshi
authors.forename: Michael Van
authors.initials: MV
authors.lastname: Linn
authors.forename: Veera Venkata
authors.initials: VV
authors.lastname: Tiruveedhula
authors.forename: Meredith E
authors.initials: ME
authors.lastname: Halcomb
authors.forename: James
authors.initials: J
authors.lastname: Cook
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Grahame
authors.forename: Harry L
authors.initials: HL
authors.lastname: June
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000428:Alcohol Drinking; D000818:Animals; D001372:Aza Compounds / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D063425:Binge Drinking; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002243:Carbolines / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D007175:Impulsive Behavior / Q000187:drug effects*; D051379:Mice; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
chemical_list: D018759:Adrenergic Uptake Inhibitors; D001372:Aza Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002243:Carbolines; D018765:Dopamine Uptake Inhibitors; D017367:Selective Serotonin Reuptake Inhibitors; C474071:1-(3,4-dichlorophenyl)-3-azabicyclo-(3.1.0)hexane hydrochloride; C454686:3-propoxy-beta-carboline; C519037:DOV 102,677
keywords: Alcohol use disorders; HAP mice; delay discounting; impulsivity; triple uptake inhibitor