Ethanol Conditioned Taste Aversion in High Drinking in the Dark Mice

Abstract

Two independent lines of High Drinking in the Dark (HDID-1, HDID-2) mice have been bred to reach high blood alcohol levels after a short period of binge-like ethanol drinking. Male mice of both lines were shown to have reduced sensitivity to develop a taste aversion to a novel flavor conditioned by ethanol injections as compared with their unselected HS/NPT founder stock. We have subsequently developed inbred variants of each line. The current experiments established that reduced ethanol-conditioned taste aversion is also seen in the inbred variants, in both males and females. In other experiments, we asked whether HDID mice would ingest sufficient doses of ethanol to lead to a conditioned taste aversion upon retest. Different manipulations were used to elevate consumption of ethanol on initial exposure. Access to increased ethanol concentrations, to multiple tubes of ethanol, and fluid restriction to increase thirst motivation all enhanced initial drinking of ethanol. Each condition led to reduced intake the next day, consistent with a mild conditioned taste aversion. These experiments support the conclusion that one reason contributing to the willingness of HDID mice to drink to the point of intoxication is a genetic insensitivity to the aversive effects of ethanol.

Timing Eclipses Amount: The Critical Importance of Intermittency in Alcohol Exposure Effects

“…They suggested that such attenuated aversive effects could permit/encourage the increases in EtOH preference/consumption seen with IAA. Consistent with this interpretation, a recent study by Crabbe and colleagues (2019) found that animals bred for high levels of drinking‐in‐the‐dark (HDID) were less sensitive to the aversive effects of EtOH, results leading the authors to suggest that HDID mice may drink more EtOH in part due to an attenuation in their genetic sensitivity to EtOH’s aversive effects (Crabbe et al, 2019).…”

“…As discussed earlier, Diaz‐Granados and Graham (2007) reported that intermittent forced vapor exposure to EtOH during adolescence resulted in greater attenuation of EtOH CTA than when vapor exposure was given continuously. Crabbe and colleagues (2019) observed that HDID mice were less sensitive to the aversive effects of EtOH than mice from the founder stock that were not selected for high drinking. It is possible that these reports of attenuated CTA could be related to the increases in NMDA receptors associated with intermittent administration given that Bienkowski and colleagues (1998) observed an inverse relationship between EtOH CTA and NR2B receptor activation.…”

Effects of Pharmacologically Targeting Neuroimmune Pathways on Alcohol Drinking in Mice Selectively Bred to Drink to Intoxication

“…Starting with a genetically heterogeneous progenitor stock (HS/NPT), selective breeding was carried out to create 2 unique High Drinking in the Dark (HDID‐1, HDID‐2) mouse lines that represent models of genetic risk for binge‐like drinking (Crabbe et al, ; Crabbe et al, ). HDID and HS/NPT mice have been extensively characterized (Barkley‐Levenson and Crabbe, ; Barkley‐Levenson and Crabbe, ; Barkley‐Levenson and Crabbe, ; Barkley‐Levenson and Crabbe, ; Barkley‐Levenson et al, ; Barkley‐Levenson et al, ; Crabbe et al, ; Crabbe et al, ; Crabbe et al, ; Crabbe et al, ; Crabbe et al, ; Crabbe et al, ; Crabbe et al, ; Ferguson et al, ; Ferguson et al, ; Fritz et al, ; Iancu et al, ; Iancu et al, ; Metten et al, ). Of particular relevance to the current studies are the findings that HDID mice exhibit behavioral impairment after DID (Crabbe et al, ), withdrawal after a single binge‐drinking session (Crabbe et al, ), and do not exhibit altered preference for saccharin or avoidance of quinine solutions (Crabbe et al, ) or alcohol clearance rates (Crabbe et al, ).…”

Alcohol Sensitivity as an Endophenotype of Alcohol Use Disorder: Exploring Its Translational Utility between Rodents and Humans

“…In addition, there is a consistently observed inverse relationship between sensitivity to the aversive effects of ethanol and ethanol consumption in both mice and rats [ 228 , 229 , 236 , 237 , 238 , 239 , 240 , 241 , 242 , 243 , 244 ]. For example, in a CTA study comparing alcohol-preferring (P) and alcohol-nonpreferring (NP) rats, it was shown that P rats displayed diminished sensitivity to the aversive effects of ethanol as compared to NP rats [ 237 ].…”