Browsing by Author "Boehm, Stephen L., II"
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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 Assessment of Acute Motor Effects and Tolerance Following Self‐Administration of Alcohol and Edible ∆9‐Tetrahydrocannabinol in Adolescent Male Mice(Wiley, 2019-11) Smoker, Michael P.; Hernandez, Maribel; Zhang, Yanping; Boehm, Stephen L., II; Psychology, School of ScienceBackground Cannabinoids and their principle psychoactive target, the cannabinoid type 1 receptor (CB1R), impact a number of alcohol‐related properties, and although alcohol and cannabis are often co‐used, particularly in adolescence, few animal models of this phenomenon exist. We modeled the co‐use of alcohol and ∆9‐tetrahydrocannabinol (THC) in adolescent mice using ingestive methods popular during this developmental period in humans, namely binge‐drinking and edible THC. With this model, we assessed levels of use, acute effects, and tolerance to each substance. Methods Adolescent male C57BL/6J mice had daily, limited access to 1 of 2 edible doughs (THC or control), to 1 of 2 fluids (ethanol (EtOH) or water), and in 1 of 2 orders (dough–fluid or fluid–dough). Home cage locomotor activity was recorded both during access and after access. On the day following the final access session, a subset of mice were assessed for functional and metabolic tolerance to alcohol using accelerating rotarod and blood EtOH concentrations, respectively. The remaining mice were assessed for tolerance to THC‐induced hypothermia, and whole‐brain CB1R expression was assessed in all mice. Results EtOH intake was on par with levels previously reported in adolescent mice. Edible THC was well‐consumed, but consumption decreased at the highest dose provided. Locomotor activity increased following EtOH intake and decreased following edible THC consumption, and edible THC increased fluid intake in general. The use of alcohol produced neither functional nor metabolic tolerance to an alcohol challenge. However, the use of edible THC impaired subsequent drug‐free rotarod performance and was associated with a reduction in THC's hypothermic effect. Conclusions Adolescent mice self‐administered both alcohol and edible THC to a degree sufficient to acutely impact locomotor activity. However, only edible THC consumption had lasting effects during short‐term abstinence. Thus, this adolescent co‐use model could be used to explore sex differences in self‐administration and the impact substance co‐use might have on other domains such as mood and cognition.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 Drinking history dependent functionality of the dorsolateral striatum on gating alcohol and quinine-adulterated alcohol front-loading and binge drinking(Elsevier, 2022) Bauer, Meredith R.; McVey, Megan M.; Boehm, Stephen L., II; Psychology, School of ScienceAfter an extended alcohol-drinking history, alcohol use can transition from controlled to compulsive, causing deleterious consequences. Alcohol use can be segregated into two distinct behaviors, alcohol seeking and alcohol taking. Expression of habitual and compulsive alcohol seeking depends on the dorsolateral striatum (DLS), a brain region thought to engage after extended alcohol access. However, it is unknown whether the DLS is also involved in compulsive-like alcohol taking. The purpose of this experiment was to identify whether the DLS gates compulsive-like binge alcohol drinking. To ask this question, we gave adult male and female C57BL/6J mice a binge-like alcohol-drinking history, which we have previously demonstrated to produce compulsive-like alcohol drinking (Bauer, McVey, & Boehm, 2021), or a water-drinking history. We then tested the involvement of the DLS on gating binge-like alcohol drinking and compulsive-like quinine-adulterated alcohol drinking via intra-DLS AMPA receptor antagonism. We hypothesized that pharmacological lesioning of the DLS would reduce compulsive-like quinine-adulterated alcohol (QuA) drinking, but not non-adulterated alcohol drinking, in male and female C57BL/6J mice. Three important findings were made. First, compulsive-like alcohol drinking is significantly blunted in cannulated mice. Because of this, we conclude that we were not able to adequately assess the effect of intra-DLS lesioning on compulsive-like alcohol drinking. Second, we found that the DLS gates binge-like alcohol drinking initially, which replicates findings in our previous work (Bauer, McVey, Germano, Zhang, & Boehm, 2022). However, following an extended alcohol history, the DLS no longer drives this behavior. Finally, alcohol and QuA front-loading is DLS-dependent in alcohol-history mice. Intra-DLS NBQX altered these drinking behaviors without altering ambulatory locomotor activity. These data demonstrate the necessity of the DLS in binge-like alcohol drinking before, but not following, an extended binge-like alcohol-drinking history and in alcohol front-loading in alcohol-history mice.Item The Effect of Alcohol Consumption History on Sensitivity and Acute Functional Tolerance to the Ataxic Effects of Alcohol in C57BL/6J Mice(Office of the Vice Chancellor for Research, 2014-04-11) Fetzer, William R.; Fritz, Brandon M.; Boehm, Stephen L., IIBinge alcohol drinking may increase the rate of development of acute functional tolerance (AFT; within session tolerance) and decrease initial sensitivity to alcohol, which in turn may increase the binge drinking behavior. The focus of this study is to determine the effects of the alcohol pre-exposure on two major responses to alcohol, sensitivity and tolerance. Sixty male C57BL/6J mice in the range of 60 to 80 days old were placed in one of the five groups varying their duration of the alcohol pre-exposure. Mice were tested for ataxic sensitivity and tolerance following 0, 1, 4, 8, or 15 days of binge alcohol consumption. The pre-exposure was conducted in the limited access drinking paradigm over the course of the dark cycle for fifteen consecutive days. The static dowel task, which requires mice to balance on an elevated wooden dowel, was utilized to determine the sensitivity, recovery length, and AFT capacity to alcohol-induced ataxia. AFT was quantified by comparing the blood alcohol concentration (BAC) at loss of balance to the BAC at recovery. Although it appeared that 4 and 15 days of repeated binge alcohol drinking reduced sensitivity to alcohol, there were no main effect of the group (p > 0.05). Analysis of the recovery of balance was significant (p < 0.05), with post-hoc tests indicating that mice with 4, 8, and 15 days of repeated binge alcohol drinking recovering the ability to balance on the static dowel earlier than the 0 group. However, the analysis of AFT was not significant, indicating that prior binge alcohol drinking, regardless of duration, did not alter development of within session tolerance. Future studies evaluating AFT using these physiological markers are needed to validate the contradictory findings and advance the scientific knowledge of the relationship between binge drinking and AFT.Item The effect of voluntary binge caffeine and ethanol co-exposure on neurobehavioral sensitivity to cocaine in male C57BL/6J mice(2016-05) Fritz, Brandon M.; Boehm, Stephen L., II; Czachowski, Cristine Lynn; Kinzig, Kimberly; Engleman, Eric A.; Grahame, Nicholas J.Recently, the co-consumption of highly caffeinated energy drinks and alcohol has become a public health concern. Consumption of these beverages has been linked to a wide variety negative consequences including alcohol poisoning, driving under the influence, physical harm, and sexual violence. The more protracted consequences of caffeinated alcohol consumption have received very little attention, however. Some evidence suggests that individuals that frequently consume energy drinks mixed with alcohol are more likely to develop an alcohol use disorder. Interestingly, both caffeine and alcohol use alone have been linked to polydrug abuse. It is therefore of interest whether combined caffeine and alcohol consumption may pose an additive risk for substance abuse. Given that both compounds can positively influence dopamine signaling in mesolimbocortical reward circuitry via different mechanisms, this is an important question to address. Psychostimulants, such as cocaine, are of particular interest considering the significant involvement of dopamine in their effects. The current project explored this possibility employing an established mouse model of binge caffeine and alcohol co-consumption. Male C57BL/6J mice underwent 14 days of daily, 2hr limited access to water, alcohol, caffeine, or combined caffeine and alcohol. Water was freely available after these sessions. In Experiment 1, mice underwent an 11-day locomotor sensitization protocol for cocaine initiating on day 15. Locomotor sensitization has been associated with a greater propensity to self-administer psychostimulants in rodents. Mice were subjected to injections of cocaine (5 or 10 mg/kg; i.p.) or saline every other day, with 15 minute activity monitoring until day 25. In Experiment 2, a separate group of mice underwent an identical drinking procedure. A conditioned place preference (CPP) protocol commenced on day 15. CPP assesses the conditioned rewarding effects of cues associated with drugs of abuse. On day 15, mice received saline injections and were immediately placed onto a neutral floor texture (paper) in the place conditioning box for 15 minutes in order to habituate the animals to the apparatus and injection procedure. Starting on day 16, mice received daily alternating systemic injections of cocaine (1 or 5 mg/kg; i.p.) and saline or saline throughout (naïve controls) and were placed onto one of two particular tactile floor cues: a metal floor with holes punched out or a grid floor made of metal rods. Mice were exposed to the other injection/floor pairing on the alternate days. Mice were placed into these activity monitors for 15 minute conditioning sessions. These sessions alternated drug and vehicle over the course of 8 days so that a total of 4 drug and 4 saline injections were given. The first place preference test occurred on day 24 wherein all mice were injected with saline and offered access to both floor textures. On day 25, mice were returned to the conditioning protocol for another 8 days and a second CPP test on day 33. The results of Experiment 1 suggested that prior caffeine consumption, irrespective of the presence of ethanol, enhanced the initial psychomotor stimulating effect of 10 mg/kg cocaine. However, prior fluid consumption history did not influence the capacity to develop locomotor sensitization. The results of Experiment 2 indicate that prior caffeine and/or ethanol consumption had no influence on the development or expression of CPP for 1 mg/kg or 5 mg/kg cocaine. Collectively, these results suggest that a history of caffeine consumption may increase the stimulant response to a moderate dose of cocaine, perhaps indicating cross-sensitization. Although the conditioned rewarding effects of cocaine were not altered by prior caffeine and/or ethanol consumption, an enhanced stimulant response may be indicative of enhanced cocaine abuse potential. This study demonstrates that moderate caffeine consumption may influence an individual’s early interactions with cocaine which may eventually influence the likelihood of later problematic use.Item GABAA Receptor Subunit Expression in Early Adolescent Mice(Office of the Vice Chancellor for Research, 2013-04-05) Anuebunwa, Nonso; Colar, Delphine; Boehm, Stephen L., IIGamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system (CNS). Of the known receptors for GABA, the pentameric GABAA receptor appears to mediate fast GABA neurotransmission in the CNS. A number of different GABAA receptor subunits have been described to date, including α1-6, β1-3, γ1-2, and δ, with the specific functionality of any one receptor dictated by the combination of subunits. Although much is known about the pattern of GABAA subunit expression across the adult brain, the pattern of such expression during the critical developmental period of adolescence, which is a time of rapid neurobiological, hormonal, and behavioral change, remains largely unknown. GABAA receptor systems play a key role in normal neural, hormonal, and behavioral function, warranting a basic understanding of adolescent-specific alterations in the pattern of subunit expression. The current project focuses on determining the pattern of mRNA expression of GABAA receptor subunits in early adolescent (postnatal day 30) versus adult (postnatal day 65) mice. The prefrontal cortex, hippocampus, nucleus accumbens, midbrain, amygdala and cerebellum were harvested at these two ages; thus far the midbrain has been the focus due to the presence of the ventral tegmental area and its well-known role in motivation, reward and drug addiction. Midbrain tissue was processed for determination of GABAA receptor subunit mRNA expression using RT-PCR. We predict that early adolescence will be associated with a unique pattern of GABAA receptor subunit expression, suggesting an important role for GABAA receptors in the neurobiological, hormonal, and behavioral profile of this developmental period in mice. Preliminary findings indicate an increase in GABAA delta subunit expression in the adult midbrain.Item Intra-dorsolateral striatal AMPA receptor antagonism reduces binge-like alcohol drinking in male and female C57BL/6J mice(Elsevier, 2022) Bauer, Meredith R.; McVey, Megan M.; Germano, Damon M.; Zhang, Yanping; Boehm, Stephen L., II; Psychology, School of ScienceThe dorsolateral striatum (DLS) is involved in addiction, reward, and alcohol related behaviors. The DLS primarily receives excitatory inputs which are gated by post-synaptic AMPA receptors. We antagonized AMPA receptors in the DLS to investigate how such modulation affects binge-like alcohol drinking in male and female C57BL/6J mice and whether an associated alcohol drinking history alters dorsomedial striatum (DMS) and DLS AMPA receptor expression. We also investigated the effect of intra-DLS NBQX on locomotor activity and saccharin drinking in mice. Mice were allowed free access to 20% alcohol for two hours each day for a total of seven days. Mice received an intra-DLS infusion of one of four concentrations of NBQX (saline, 0.15, 0.5, or 1.5 μg/side), an AMPA receptor antagonist, immediately prior to alcohol access on day 7. Two-hour binge alcohol intakes, locomotor activity, and blood alcohol concentrations were determined. Intra-DLS NBQX reduced binge-like alcohol drinking in a U-shaped manner in male and female mice. Intake predicted blood alcohol concentration, and locomotor activity was not affected. In a follow up experiment, we assessed whether the most effective NBQX concentration for reducing alcohol consumption also reduced saccharin drinking, finding intra-DLS NBQX did not alter saccharin drinking in male and female mice. These data suggest that AMPA receptors in the DLS play a role in the modulation of binge-like alcohol drinking. These findings further validate the importance of the DLS for alcohol related behaviors and alcohol use disorder.Item Low-level developmental lead exposure does not predispose to adult alcohol self-administration, but does increase the risk of relapsing to alcohol seeking in mice: Contrasting role of GLT1 and xCT brain expression(Elsevier, 2020-12-15) Rangel-Barajas, Claudia; Coronel, Israel; Zhang, Yanping; Hernández, Maribel; Boehm, Stephen L., II; Psychology, School of ScienceLead (Pb) is a neurotoxic heavy metal pollutant. Despite the efforts to reduce Pb environmental exposure and to prevent Pb poisoning, exposure in human populations persists. Studies of adults with history of childhood lead exposure have consistently demonstrated cognitive impairments that have been associated with sustained glutamate signaling. Additionally, some clinical studies have also found correlations between Pb exposure and increased proclivity to drug addiction. Thus, here we sought to investigate if developmental Pb exposure can increase propensity to alcohol consumption and relapse using an alcohol self-administration paradigm. Because Pb exposure is associated with increased glutamatergic tone, we also studied the effects on the expression of synaptic and non-synaptic glutamate transporters in brain regions associated with drug addiction such as the nucleus accumbens (NAc), dorsomedial striatum (DMS), dorsolateral striatum (DLS), and medial prefrontal cortex (mPFC). We found that while developmental Pb exposure did not increase risk for alcohol self-administration, it did play a role in relapsing to alcohol. The effects were associated with differential expression of the glutamate transporter 1 (GLT1) and the glutamate/cystine antiporter (xCT). In the NAc and DLS the expression of GLT1 was found to be significantly reduced, while no changes were found in DMS or mPFC. Contrastingly, xCT was found to be upregulated in NAc but downregulated in DLS, with no changes in DMS or mPFC. Our data suggest that lead exposure is involved in relapse to alcohol seeking, an effect that could be associated with downregulation of GLT1 and xCT in the DLS.