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

Abstract

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 two hour period, three hours 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-hour 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.

Intra-nucleus accumbens shell injections of R(+)- and S(−)-baclofen bidirectionally alter binge-like ethanol, but not saccharin, intake in C57Bl/6J mice

“…Further, Agmo and Paredes [45, 46] demonstrated that while baclofen reduced sociosexual behavior and locomotion, other drugs also decreased locomotion without affecting sociosexual behavior, suggesting that reductions in locomotor activity are not causative of reductions in motivated behavior. Using home-cage locomotor activity boxes, our lab has recently demonstrated that systemic administration of R(+)- and S(-)-baclofen do not alter locomotor activity during ethanol or saccharin consumption in the same 5 day DID paradigm used in the current study [47]. Thus, our results, taken with those of Spano et al and Agmo and Paredes, suggest that baclofen is working to reduce ethanol consumption via mechanisms alternative to those producing sedation.…”

“…Working to overcome negative drug effects to consume saccharin would explain why animals drank even after receiving R(+)-baclofen, but it does not explain why S(-)-baclofen did not produce an increase in saccharin consumption or why aCSF reduced saccharin intake. Further, our lab has observed reductions in saccharin intake following systemic R(+)-baclofen [47], so concluding that R(+)-baclofen is unable to reduce saccharin consumption would seem unsatisfactory. Perhaps, the best explanation is that the NACsh is not responsible for the control of saccharin intake, likely due to a combination of a transfer of control to another brain region and the possible lack of dopamine response on Day 5.…”

“…Initial R(+)-baclofen doses for this study were based on those previously used by our lab [23,47]. Pilot doses of 0.01, 0.02, and 0.04 μg of R(+)-baclofen suggested that 0.04 μg/side would be the lowest dose to reduce ethanol intake, whereas 0.02 μg/side would be the highest dose that would not affect intake.…”

Developing a model of limited-access nicotine consumption in C57Bl/6J mice

“…The remaining 32 animals were administered 0, 0.75, 1.5, or 3 mg/kg of mecamylamine. Doses were based on previous ethanol DID findings (Hendrickson et al, 2009; Kasten et al, 2015). On day 5, drug was administered immediately prior to bottles on and a fluid intake was monitored at bottles-on, hour 1, and hour 2 to observe time-specific effects on intake.…”

“…Mecamylamine is often used to precipitate nicotine withdrawal whereas baclofen attenuates the negative effects of nicotine withdrawal (Varani et al, 2014). Both of these drugs reduce ethanol intake in the DID paradigm and baclofen has been shown to reduce smoking behavior in a clinical trial (Franklin et al, 2009; Hendrickson et al, 2009; Kasten et al, 2015; Leggio et al, 2015). Finally, we sought to characterize whether B6 mice would co-consume nicotine and alcohol, as is often the case in human addiction (National Institute on Alcohol Abuse and Alcoholism, 2007), and whether co-consumption could be pharmacologically manipulated.…”