Mouse strain differences in punished ethanol self-administration

Abstract

Determining the neural factors contributing to compulsive behaviors such as alcohol-use disorders (AUDs) has become a significant focus of current preclinical research. Comparison of phenotypic differences across genetically distinct mouse strains provides one approach to identify molecular and genetic factors contributing to compulsive-like behaviors. Here we examine a rodent assay for punished ethanol self-administration in four widely used inbred strains known to differ on ethanol-related behaviors: C57BL/6J (B6), DBA/2J (D2), 129S1/SvImJ (S1), and BALB/cJ (BALB). Mice were trained in an operant task (FR1) to reliably lever-press for 10% ethanol using a sucrose-fading procedure. Once trained, mice received a punishment session in which lever pressing resulted in alternating ethanol reward and footshock, followed by tests to probe the effects of punishment on ethanol self-administration. Results indicated significant strain differences in training performance and punished attenuation of ethanol self-administration. S1 and BALB showed robust attenuation of ethanol self-administration after punishment, whereas behavior in B6 was attenuated only when the punishment and probe tests were conducted in the same contexts. By contrast, D2 were insensitive to punishment regardless of context, despite receiving more shocks during punishment and exhibiting normal footshock reactivity. Additionally, B6, but not D2, reduced operant self-administration when ethanol was devalued with a bitter tastant. B6 and D2 showed devaluation of sucrose self-administration, and punished suppression of sucrose seeking was context dependent in both the strains. While previous studies have demonstrated avoidance of ethanol in D2, particularly when ethanol is orally available from a bottle, current findings suggest this strain may exhibit heightened compulsive-like self-administration of ethanol, although there are credible alternative explanations of the phenotype of this strain. In sum, these findings offer a foundation for future studies examining the neural and genetic factors underlying AUDs.

Prefrontal Regulation of Punished Ethanol Self-administration

“…We first examined the behavioral profile of mice undergoing in vivo neuronal recordings. Replicating previous observations (37)(38)(39), the rate of EtOH lever pressing was significantly suppressed during punishment and probe testing, compared with the unpunished baseline period of the punishment session ( Figure 1B, C). The number of shocks received inversely predicted suppression on probe (i.e., positive correlation between EtOH-SA during punishment and probe [r = .61, p = .003]), showing that the degree of suppression during probe testing was not due to the number of shocks received.…”

“…Mice were trained in a Med Associates operant chamber (Med Associates, Inc., Fairfax, VT) to respond on the left of two levers on a continuous schedule of reinforcement to earn sucrose pellets during 40-minute sessions (the right, "inactive" lever had no programed consequences) until the criterion was met ($35 rewards), as previously described (37)(38)(39). The pellet was then substituted with a progression of 10-mL liquid rewards ("sucrose fading"; 10% sucrose, 10% sucrose 1 10% EtOH, 5% sucrose 1 10% EtOH, 10% EtOH).…”

Chronic Ethanol During Adolescence Impacts Corticolimbic Dendritic Spines and Behavior

“…Multiple measures of operant responding for food reward were assessed following CIE. Mice were first given CIE exposure for 4 weeks and operant testing began 3 days after the completion of CIE exposure (for schematic of experimental design, see Fig. A ) and continued for 5 to 6 weeks using methods previously described (Halladay et al., ; Radke et al., , ). Mice were maintained at ~85% of their free‐feeding body weight throughout testing to motivate performance.…”

Variability in prescription opioid intake and reinforcement amongst 129 substrains

“…While the active-hole responding exhibited by 129S1 and 129X1 mice during early training was superimposable, 129S1 mice exhibited very poor hole discrimination (Figs. Further, 129S1 can be trained to respond for food pellet, sucrose and alcohol reinforcement (Halladay et al 2017), arguing intact operant-conditioning processes in this substrain. The poor hole discrimination exhibited by 129S1 mice does not likely reflect some general deficit in reward processing or operant-learning as 129S1 mice exhibit: unconditioned approach towards appetitive, nondrug reinforcers similarly to other 129-unrelated isogenic mouse strains (Malkesman et al 2010) and comparable voluntary intake of very low-dose oxycodone and fentanyl vs. the other 129 substrains (Fig.…”

“…1). Further, 129S1 can be trained to respond for food pellet, sucrose and alcohol reinforcement (Halladay et al 2017), arguing intact operant-conditioning processes in this substrain. Thus, future studies will examine for the generalization of phenotype across different oxycodone training-doses, as well as across other drug and nondrug reinforcers to probe the opioid-specificity of their low oxycodone reinforcement phenotype.…”