Bidirectional enantioselective effects of the GABAB receptor agonist baclofen in two mouse models of excessive ethanol consumption

The GABAB receptor agonist baclofen has been studied extensively in preclinical models of alcohol-use disorders, yet results on its efficacy have been uncertain. Racemic baclofen, which is used clinically, can be broken down into separate enantiomers of the drug. Baclofen has been shown to produce enantioselective effects in behavioral assays, including those modeling reflexive and sexual behavior. The current studies sought to characterize the enantioselective effects of baclofen in two separate models of ethanol consumption. The first was a Drinking-in-the-Dark procedure that provides "binge-like" ethanol access to mice by restricting access to a 2-h period, 3 h into the dark cycle. The second was a two-bottle choice procedure that utilized selectively bred High Alcohol Preferring 1 (HAP1) mice to model chronic ethanol access. HAP1 mice are selectively bred to consume pharmacologically relevant amounts of ethanol in a 24-h two-bottle choice paradigm. The results showed that baclofen yields enantioselective effects on ethanol intake in both models, and that these effects are bidirectional. Total ethanol intake was decreased by R(+)-baclofen, while total intake was increased by S(-)-baclofen in the binge-like and chronic drinking models. Whereas overall binge-like saccharin intake was significantly reduced by R(+)-baclofen, chronic intake was not significantly altered. S(-)-baclofen did not significantly alter saccharin intake. Neither enantiomer significantly affected locomotion during binge-like reinforcer consumption. Collectively, these results demonstrate that baclofen produces enantioselective effects on ethanol consumption. More importantly, the modulation of consumption is bidirectional. The opposing enantioselective effects may explain some of the variance seen in published baclofen literature

Development of Cross-Tolerance Between Ethanol and Baclofen in C57Bl/6J Mice

poster abstractAlcohol is one of the most commonly used drugs of abuse. One criteria of alcohol abuse is the development of tolerance, meaning that more of the substance has to be ingested to produce the same pharmacological or behavioral effects. The phenomenon of cross-tolerance is when use of one substance leads to tolerance to an unused substance. Ethanol has also been shown to produce cross-tolerance to other drugs, such as benzodiazepines. The purpose of the current study was to investigate whether prior binge-like ethanol exposure in C57Bl/6J (B6) mice would produce a cross-tolerance to the locomotor sedative effects of the GABAB agonist R(+)-baclofen. We exposed 32 B6 male mice to a limited-access binge-like drinking procedure. Mice received daily access to either 0.2% saccharin or 20% ethanol for 2 hours, 3 hours into the dark cycle each day. There were four groups; 5 days of saccharin or ethanol access, and 10 days of saccharin or ethanol access. Baseline locomotor recordings were taken before ethanol drinking using Versamax activity monitors. Twenty-two hours following the last day of binge-like ethanol access, all animals received a 10mg/kg injection of R(+)-baclofen and Versamax activity was recorded for 1 hour. Sedation scores were calculated by subtracting the challenge day locomotor scores from the baseline locomotor scores. There was no effect of length of exposure (5 versus 10 days) or fluid type (ethanol versus saccharin) on total sedation scores (p<.05). A Length of Exposure*Fluid Type*Time-Bin ANOVA looking at sedation scores in 5 minute bins revealed a trend towards an omnibus interaction, but it did not reach significance (p=0.64). There was a main effect of time, with sedation scores being lower immediately following the injection (9<.05). These results indicate that ethanol does not produce a locomotors cross-tolerance to R(+)-baclofen