Enhanced alcohol self-administration and reinstatement in a highly impulsive, inattentive recombinant inbred mouse strain

Abstract

Deficits in executive control have frequently been associated with alcohol use disorder. Here we investigated to what extent pre-existing genetically encoded levels of impulsive/inattentive behavior associate with motivation to take alcohol and vulnerability to cue-induced reinstatement of alcohol seeking in an operant self-administration paradigm. We took advantage of BXD16, a recombinant inbred strain previously shown to have enhanced impulsivity and poor attentional control. We compared BXD16 with C57BL/6J mice in a simple choice reaction time task (SCRTT) and confirmed its impulsive/inattentive phenotype. BXD16 mice were less active in a novel open field (OF), and were equally active in an automated home cage environment, showing that increased impulsive responding of BXD16 mice could not be explained by enhanced general activity compared to C57BL/6J mice. After training in a sucrose/alcohol fading self-administration procedure, BXD16 showed increased motivation to earn 10% alcohol solution, both under fixed ratio (FR1) and progressive ratio (PR2) schedules of reinforcement. Responding on the active lever readily decreased during extinction training with no apparent differences between strains. However, upon re-exposure to alcohol-associated cues, alcohol seeking was reinstated to a larger extent in BXD16 than in C57BL/6J mice. Although further studies are needed to determine whether impulsivity/inattention and alcohol seeking depend on common or separate genetic loci, these data show that in mice enhanced impulsivity coincides with increased motivation to take alcohol, as well as relapse vulnerability.

Cue-induced reinstatement of alcohol-seeking behavior is associated with increased CaMKII T286 phosphorylation in the reward pathway of mice

“…These behavioral data demonstrate cue-induced reinstatement of alcohol-seeking behavior on the previously active lever that was associated with alcohol and cue presentation. Cue-induced reinstatement of approximately 50% of baseline alcohol reinforced responding is generally consistent with prior studies in alcohol preferring P-rats (Cannady et al, 2013; Schroeder et al, 2008) and C57BL/6J mice (Tsiang and Janak, 2006; Loos et al, 2013 #777).…”

Alcohol-Preferring Rats Show Goal Oriented Behaviour to Food Incentives but Are Neither Sign-Trackers Nor Impulsive

“…For instance, alcohol-naive C57BL/6J mice, which naturally show high levels of alcohol preference, also show higher levels of impulsivity in the 5-CSRTT compared with DBA2/J mice, a naturally alcohol-avoiding strain [ 8 ]. Furthermore, the BXD16 recombinant inbred mouse strain, characterised by an impulsive/inattentive phenotype in the 5-CSRTT also showed higher motivation to obtain an alcohol solution and enhanced cue-induced relapse of alcohol seeking [ 9 ].…”

Prenatal ethanol increases ethanol intake throughout adolescence, alters ethanol‐mediated aversive learning, and affects μ but not δ or κ opioid receptor mRNA expression

“…As already noted, one limitation was the slightly sweetened water that was used as the vehicle during the first 2 weeks. The concentrations of sucrose, however, were much lower than those of the widely used sucrose‐fading technique that is used in adult subjects (Loos et al ., ), and the differences between the PEE and PV groups persisted after fading was complete. Moreover, ingestion from the vehicle bottle and overall fluid intake were unaffected by PEE.…”