Browsing by Author "Kasten, Chelsea R."
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Item Acute Cannabinoids Produce Robust Anxiety-Like and Locomotor Effects in Mice, but Long-Term Consequences Are Age- and Sex-Dependent(Frontiers Media, 2019-02-20) Kasten, Chelsea R.; Zhang, Yanping; Boehm, Stephen L., II; Department of Psychology, School of ScienceThe rise in cannabinoid legalization and decriminalization in the US has been paired with an increase in adolescents that perceive marijuana as a "no risk" drug. However, a comprehensive review of human literature indicates that cannabinoid usage may have both beneficial and detrimental effects, with adolescent exposure being a critical window for harming cognitive development. Although the cannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are often used together for recreational and medical purposes, no study has previously observed the acute and long-lasting effects of THC+CBD in a battery of behavioral assays analogous to subjective human reports. The current study observed the acute and long-term effects of THC, CBD, and THC+CBD on object recognition memory, anxiety-like behavior, and activity levels in adolescent and adult mice of both sexes. Acute THC alone and in combination with CBD resulted in robust effects on anxiety-like and locomotor behavior. A history of repeated cannabinoid treatment followed by a period without drug administration resulted in minimal effects in these behavioral assays. Most notably, the strongest effects of repeated cannabinoid treatment were seen in adult females administered THC+CBD, which significantly impaired their object recognition. No effects of repeated cannabinoid history were present on hippocampal protein expression. These studies represent a detailed examination of age- and sex-effects of acute and repeated cannabinoid administration. However, the acute and long-term effects of THC with and without CBD on additional behaviors in adolescents and adults will need to be examined for a more complete picture of these drug effects.Item Bidirectional enantioselective effects of the GABAB receptor agonist baclofen in two mouse models of excessive ethanol consumption(Elsevier, 2015-02) Kasten, Chelsea R.; Blasingame, Shelby N.; Boehm, Stephen L.; Department of Psychology, School of ScienceThe 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.Item Concomitant Caffeine Increases Binge Consumption of Ethanol in Adolescent and Adult Mice, But Produces Additive Motor Stimulation Only in Adolescent Animals(Wiley, 2016-06) Fritz, Brandon M.; Quoilin, Caroline; Kasten, Chelsea R.; Smoke, Michael; Boehm, Stephen L., II; Psychology, School of ScienceBACKGROUND: Binge co-consumption of highly caffeinated energy drinks with alcohol (ethanol [EtOH]) has become a common practice among adolescents/young adults and has been associated with an increased incidence of hazardous behaviors. Animal models are critical in advancing our understanding the neurobehavioral consequences of this form of binge drinking. Surprisingly, virtually no work has explored caffeine and EtOH co-consumption or its long-term consequences in adolescent animals. The primary objective of the current study was to extend a previously established mouse model of voluntary binge caffeine and EtOH co-consumption to explore adolescent consumption and responses compared to adults. METHODS: Adolescent and adult male C57BL/6J mice had daily limited access to caffeine (0.03% w/v), EtOH (20% v/v), a combined EtOH/caffeine solution, or water for 14 days via the binge-like drinking paradigm, drinking-in-the-dark (DID). Home cage locomotor activity was measured during DID in a subset of mice. Following DID, all mice rested for 18 days so that adolescents reached adulthood, whereupon all mice underwent 7 days of continuous access 2-bottle choice drinking for 10% (v/v) EtOH or water. RESULTS: Co-consumption with caffeine significantly increased EtOH intake and resultant blood ethanol concentrations in both adolescent and adult mice. In addition, adolescent mice exhibited a uniquely robust locomotor stimulant response to caffeine and EtOH co-consumption. Later EtOH intake and preference was not influenced, however, by prior fluid consumption history via DID. CONCLUSIONS: Together with findings from the human literature, our results suggest that caffeine co-consumption may positively influence binge alcohol consumption in adolescents/young adults. Importantly, this age group may be particularly sensitive to the additive stimulant effects of caffeinated alcohol consumption, an effect which may be related to the high incidence of associated negative outcomes in this population. These observations are particularly concerning considering the heightened plasticity of the adolescent brain.Item Development of Cross-Tolerance Between Ethanol and Baclofen in C57Bl/6J Mice(Office of the Vice Chancellor for Research, 2014-04-11) Blasingame, Shelby N.; Kasten, Chelsea R.; Boehm, Stephen L., IIAlcohol 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.Item Identifying the role of pre-and postsynaptic GABAB receptors in behavior.(Elsevier, 2015-10) Kasten, Chelsea R.; Boehm, Stephen L.; Department of Psychology, School of ScienceAlthough many reviews exist characterizing the molecular differences of GABAB receptor isoforms, there is no current review of the in vivo effects of these isoforms. The current review focuses on whether the GABAB1a and GABAB1b isoforms contribute differentially to behaviors in isoform knockout mice. The roles of these receptors have primarily been characterized in cognitive, anxiety, and depressive phenotypes. Currently, the field supports a role of GABAB1a in memory maintenance and protection against an anhedonic phenotype, whereas GABAB1b appears to be involved in memory formation and a susceptibility to developing an anhedonic phenotype. Although GABAB receptors have been strongly implicated in drug abuse phenotypes, no isoform-specific work has been done in this field. Future directions include developing site-specific isoform knockdown to identify the role of different brain regions in behavior, as well as identifying how these isoforms are involved in development of behavioral phenotypes.Item Intra-nucleus accumbens shell injections of R(+)- and S(-)-baclofen bidirectionally alter binge-like ethanol, but not saccharin, intake in C57Bl/6J mice(Elsevier, 2014-10-01) Kasten, Chelsea R.; Boehm II, Stephen L.; Department of Psychology, School of ScienceThe 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.Item Preclinical Medication Development: New Targets and New Drugs(Wiley, 2016-07) Kasten, Chelsea R.; Boehm, Stephen L., II; Psychology, School of ScienceItem Selectively bred crossed high-alcohol-preferring mice drink to intoxication and develop functional tolerance, but not locomotor sensitization during free-choice ethanol access(Wiley Blackwell (Blackwell Publishing), 2014-01) Matson, Liana M.; Kasten, Chelsea R.; Boehm, Stephen L.; Grahame, Nicholas J.; Department of Psychology, IU School of ScienceBACKGROUND: Crossed high-alcohol-preferring (cHAP) mice were selectively bred from a cross of the HAP1 × HAP2 replicate lines and demonstrate blood ethanol concentrations (BECs) during free-choice drinking reminiscent of those observed in alcohol-dependent humans. In this report, we investigated the relationship between free-choice drinking, intoxication, tolerance, and sensitization in cHAP mice. We hypothesized that initially mice would become ataxic after drinking alcohol, but that increased drinking over days would be accompanied by increasing tolerance to the ataxic effects of ethanol (EtOH). METHODS: Male and female cHAP mice had free-choice access to 10% EtOH and water (E), while Water mice (W) had access to water alone. In experiment 1, the first drinking experience was monitored during the dark portion of the cycle. Once E mice reached an average intake rate of ≥1.5 g/kg/h, they, along with W mice, were tested for footslips on a balance beam, and BECs were assessed. In experiments 2, 3, and 4, after varying durations of free-choice 10% EtOH access (0, 3, 14, or 21 days), mice were challenged with 20% EtOH and tested for number of footslips on a balance beam or locomotor stimulant response. Blood was sampled for BEC determination. RESULTS: We found that cHAP mice rapidly acquire alcohol intakes that lead to ataxia. Over time, cHAP mice developed behavioral tolerance to the ataxic effects of alcohol, paralleled by escalating alcohol consumption. However, locomotor sensitization did not develop following 14 days of free-choice EtOH access. CONCLUSIONS: Overall, we observed increases in free-choice drinking with extended alcohol access paralleled by increases in functional tolerance, but not locomotor sensitization. These data support our hypothesis that escalating free-choice drinking over days in cHAP mice is driven by tolerance to alcohol's behavioral effects. These data are the first to demonstrate that escalating free-choice consumption is accompanied by increasing alcohol tolerance. In addition to buttressing the hypothesized importance of tolerance in drinking, our findings suggest that cHAP mice may be a unique, translational resource for studying tolerance as a contributor to and consequence of chronic, excessive EtOH consumption.Item Short-Term Genetic Selection for Adolescent Locomotor Sensitivity to Delta9-Tetrahydrocannabinol (THC)(Springer Nature, 2018-05) Kasten, Chelsea R.; Zhang, Yanping; Mackie, Ken; Boehm, Stephen L., II; Psychology, School of ScienceCannabis use is linked to positive and negative outcomes. Identifying genetic targets of susceptibility to the negative effects of cannabinoid use is of growing importance. The current study sought to complete short-term selective breeding for adolescent sensitivity and resistance to the locomotor effects of a single 10 mg/kg THC dose in the open field. Selection for THC-locomotor sensitivity was moderately heritable, with the greatest estimates of heritability seen in females from the F2 to S3 generations. Selection for locomotor sensitivity also resulted in increased anxiety-like activity in the open field. These results are the first to indicate that adolescent THC-locomotor sensitivity can be influenced via selective breeding. Development of lines with a genetic predisposition for THC-sensitivity or resistance to locomotor effects allow for investigation of risk factors, differences in consequences of THC use, identification of correlated behavioral responses, and detection of genetic targets that may contribute to heightened cannabinoid sensitivity.Item Systemic administration of racemic baclofen reduces both acquisition and maintenance of alcohol consumption in male and female mice(Elsevier, 2022) Bauer, Meredith R.; Hernández, Maribel; Kasten, Chelsea R.; Boehm, Stephen L., II; Psychology, School of ScienceBaclofen is a GABAB receptor agonist with proposed use as a treatment for alcohol use disorder (AUD). In preclinical studies, racemic baclofen decreases alcohol consumption in both mice and rats; however, there is a significant disparity in the efficacy of the drug across species. We previously demonstrated that baclofen is enantioselective, with the racemic enantiomer successfully reducing binge-like alcohol consumption during Drinking-in-the-Dark (DID) in C57BL/6J (B6) mice, as well as 24-h consumption during two-bottle choice (2BC) preference drinking in replicate 1 High Alcohol Preferring (HAP) mice. Here we extend these findings by investigating the effects of racemic baclofen on the acquisition and maintenance of alcohol consumption, locomotor activity, and saccharin drinking in two different mouse genotypes and drinking paradigms. Adult male and female B6 mice were allowed free access to 20% (v/v) alcohol for 2 h daily in a 14-day DID procedure. Adult male and female replicate 2 HAP (HAP2) mice were allowed 24-h access to 10% (v/v) alcohol versus tap water in a 2BC procedure for 14 days. Systemic injections of baclofen (0.0 or 3.0 mg/kg) were given 3 h into the dark cycle on days 1–5 in alcohol acquisition experiments and days 6–10 in alcohol maintenance experiments. We found that racemic baclofen significantly reduces acquisition of DID and 2BC alcohol drinking in male and female B6 and HAP2 mice, whereas it only significantly reduces the maintenance of DID alcohol intake in B6 mice. Racemic baclofen did not alter home cage locomotor activity but did alter saccharin intake, suggesting it may have nonspecific effects. The current data add to literature suggesting that smaller doses of racemic baclofen may be an effective treatment of AUD. Future work should focus on the longitudinal efficacy of racemic baclofen in high-drinking mouse genotypes to further investigate whether it is effective for those with a genetic predisposition to AUD.