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Kasten C.R.,Indiana University - Purdue University Indianapolis | Boehm S.L.,Indiana University - Purdue University Indianapolis | Boehm S.L.,Indiana Alcohol Research Center
Behavioural Brain Research | Year: 2014

The GABAB agonist baclofen has been widely researched clinically and preclinically as a treatment of alcohol use disorders (AUDs). However, the efficacy of baclofen remains uncertain. The clinically used racemic compound can be separated into separate enantiomers. These enantiomers have produced different profiles in behavioral assays, with the S- compound often being ineffective compared to the R- compound, or the S- compound antagonizing the effects of the R- compound. We have previously demonstrated that the R(+)-baclofen enantiomer decreases binge-like ethanol intake in the Drinking-in-the-Dark (DID) paradigm, whereas the S(-)-baclofen enantiomer increases ethanol intake. One area implicated in drug abuse is the nucleus accumbens shell (NACsh). The current study sought to define the role of the NACsh in the enantioselective effects of baclofen on binge-like ethanol consumption by directly microinjecting each enantiomer into the structure. Following bilateral cannulation of the NACsh, C57Bl/6J mice were given 5 days of access to ethanol or saccharin for 2h, 3h into the dark cycle. On Day 5 mice were given an injection of aCSF, 0.02 R(+)-, 0.04R(+)-, 0.08 S(-)-, or 0.16 S(-)-baclofen (μg/side dissolved in 200nl of aCSF). It was found that the R(+)-baclofen dose-dependently decreased ethanol consumption, whereas the high S(-)-baclofen dose increased ethanol consumption, compared to the aCSF group. Saccharin consumption was not affected. These results further confirm that GABAB receptors and the NACsh shell are integral in mediating ethanol intake. They also demonstrate that baclofen displays bidirectional, enantioselective effects which are important when considering therapeutic uses of the drug. © 2014 Elsevier B.V. Source

Kasten C.R.,University of Indianapolis | Blasingame S.N.,University of Indianapolis | Boehm S.L.,University of Indianapolis | Boehm S.L.,Indiana Alcohol Research Center
Alcohol | Year: 2015

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, 3h 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. © 2015 Elsevier Inc. Source

Kasten C.R.,University of Indianapolis | Frazee A.M.,University of Indianapolis | Boehm S.L.,University of Indianapolis | Boehm S.L.,Indiana Alcohol Research Center
Pharmacology Biochemistry and Behavior | Year: 2016

Although United States smoking rates have been on the decline over the past few decades, cigarette smoking still poses a critical health and economic threat. Very few treatment options for smoking exist, and many of them do not lead to long-term abstinence. Preclinical models are necessary for understanding the effects of nicotine and developing treatments. Current self-administration models of nicotine intake may require surgical procedures and often result in low levels of intake. Further, they do not lend themselves to investigating treatments. The current study sought to develop a limited-access model of nicotine intake using the Drinking-in-the-Dark paradigm, which results in high levels of binge-like ethanol consumption that can be pharmacologically manipulated. The present study found that mice will consume nicotine under a range of parameters. Intakes under the preferred condition of 0.14 mg/ml nicotine in 0.2% saccharin reached over 6 mg/kg in two hours and were reduced by an injection of R(+)-baclofen. Mecamylamine did not significantly affect nicotine consumption. As nicotine and ethanol are often co-abused, nicotine intake was also tested in the presence of ethanol. When presented in the same bottle, mice altered nicotine intake under various concentrations to maintain consistent levels of ethanol intake. When nicotine and ethanol were presented in separate bottles, mice greatly reduced their nicotine intake while maintaining ethanol intake. In conclusion, these studies characterize a novel model of limited-access nicotine intake that can be pharmacologically manipulated. © 2016 Elsevier Inc. Source

News Article | August 30, 2016
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If you have an addiction, the source of your craving may be a pea-sized structure deep inside the right side of your brain, according to scientists at the Indiana University School of Medicine. Using two different kinds of advanced brain imaging techniques (PET and fMRI), the researchers compared the results of giving beer drinkers a taste of their favorite beer versus a sports drink. After tasting the beer the participants reported increased desire to drink beer, whereas the sports drink did not provoke as much desire for beer. The brain scans also showed that the beer flavor induced more activity in both frontal lobes and in the right ventral striatum of the subjects' brains than did the sports drink. More specifically, both methods of brain imaging showed increased activity in the right ventral striatum, a deep structure inside the brain that is linked to motivated behavior and reward. The researchers previously showed that beer flavor triggered dopamine release; the addition of fMRI showed that craving for alcohol correlated with frontal as well as right ventral striatum activation. The study was published recently in the journal Alcoholism: Clinical and Experimental Research. In an earlier study of 49 men, the research team, led by David A. Kareken, Ph.D., professor of neurology at the IU School of Medicine and the deputy director of the Indiana Alcohol Research Center, found that just the taste of beer, without any intoxicating effects of alcohol, was enough to cause the release of dopamine, a brain neurotransmitter. Much research has linked dopamine to consumption of drugs of abuse. The new study was conducted with 28 beer drinkers who had participated in the first study, who then underwent functional magnetic resonance imaging - fMRI scans - during the separate beer and Gatorade tastings. "We believe this is the first study to use multiple brain imaging modalities to reveal both increased blood oxygen levels and dopamine activity in response to the taste of an alcoholic beverage," said Brandon Oberlin, assistant research professor of neurology and first author of the paper. "The combination of these two techniques in the same subjects strengthens the evidence that these effects may be strongest in the right ventral striatum. "Our results indicate that the right ventral striatum may be an especially important area for addiction research," Oberlin said.

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