Browsing by Author "Boehm, Stephen"
Now showing 1 - 10 of 13
Results Per Page
Sort Options
Item Chronic consumption of a high-fat diet: investigation of negative consequences(2018-07) Vigil, Daniel W.; Boehm, StephenChronic consumption of a high-fat diet is a lifestyle factor that increases the risk for cognitive impairment (Granholm et al., 2008; Greenwood & Winocur, 2005; Mattson, 2004; Winocur & Greenwood, 2005). A high-fat diet appears to facilitate cognitive impairment through the promotion of insulin resistance (Greenwood & Winocur, 2005; Stranahan et al., 2008; Winocur & Greenwood, 2005). A gap in the literature is an established timeframe of the progression and underlying mechanism, which study in animals would better afford. Furthermore, A limited number of studies have investigated the relationship between a high-fat diet and behavioral dysregulation such as anxiety and depression. The 1st aim of the study was to determine if consumption of a high-fat diet leads to cognitive impairment and behavioral dysfunction at 3, 8, or 13 weeks of consumption. The 2nd aim was to determine if cholesterol levels and HBP activity are aberrantly increased in specific regions in mice that display feeding induced cognitive/behavioral dysfunction. Consumption of the experimental specialty diets produced a number of significant behavioral effects. These significant effects began to emerge after only 3 weeks of low-and high-fat feeding with increased anxiety-like behavior displayed higher in the high-fat diet group for the Elevated Plus Maze and Open Field Test. There was increased thigmotactic behavior and floating in the low-fat diet group in the Morris Water Maze (MWM) task, therefore making cognitive assessment uninterpretable. This pattern in the behavioral tasks were more robust in the 8 week group and alleviated in the 13 week group. There was only a significant difference in depression-like symptoms in the Forced Swim (FS) Task in the 3 week group. Cholesterol analysis is still under review in Dr. Elmendorf’s lab to correlate cholesterol levels and cognitive/behavioral impairment.Item Does binge drinking induce PMDD-like dysfunction for female C57BL/6J mice? : implications for sex differences in addiction vulnerability(2014) Melón, Laverne C.; Boehm, Stephen; Czachowski, Cristine; Grahame, Nicholas J.; Swithers, Susan E.It has traditionally been posited that women show a "telescoped" development of alcohol use disorders (Kuhn, 2011). In particular, a number of clinical studies support striking sex differences in the progression from initial use of alcohol to dependence on the compound; with women showing a faster progression through landmark events associated with the development of alcohol addiction (Randall et al., 1999). However, recent studies have challenged this tenet (Keyes et al., 2010). The work presented herein was designed to determine whether females are indeed more vulnerable to the development of behavioral maladaptations following binge drinking and whether sex differences in GABA(A) receptor regulation might underlie this vulnerability. Using a mouse model of binge drinking this dissertation established that, compared to males, females escalate their binge drinking at a faster rate and maintain altered responsivity to the locomotor effects of alcohol after extended abstinence from binge drinking. Female mice also displayed significant increases in ethanol preference and intake in a continuous, two-bottle choice protocol following a shorter history of binge drinking than males. The final goal was to determine if binge drinking results in unique patterns of anxiety- or depressive-like symptoms in males and females and whether these behaviors would be associated with the dimorphic regulation of GABAA receptor subunits across the prefrontal cortex and hippocampus. Male binge drinkers displayed anxiety-like behavior during early withdrawal that dissipated after 2 weeks of abstinence. There were no significant changes in the expression of delta or gamma2 GABAA receptor subunit mRNA at this time point in the regions analyzed. Females also showed temporary anxiety-like behavior during early withdrawal from binge drinking. Additionally, females displayed significant depressive-like behavior after 2 weeks of abstinence from binge drinking. In particular, diestrus-phase females displayed significantly greater immobility in the forced-swim test after ethanol exposure and no longer maintained the reduced swim-time behavior associated with this phase of the cycle at baseline (when compared to the estrus-phase). qPCR analysis of hippocampal tissues from diestrus females supported a significant reduction in expression of gamma2 GABA(A) subunit mRNA after binge drinking. This effect was not noted for RNA isolated from hippocampal tissues taken during the estrus phase of bingers. These final data suggest possible interaction of estrous-cycle and binge drinking history that may result in the unique expression of deficits following binge drinking for females. Taken together, this work supports sex and estrous dependent effects of binge drinking on behavior and gene regulation.Item Effects of Developmental Low-Level Lead Exposure on Voluntary Alcohol Consumption and Drug-Induced Behavioral Sensitization in Adulthood(2020-12) Hernández, Maribel; Boehm, Stephen; Filippelli, Gabriel; Graham, NicholasLead (Pb) is one of the most harmful and most abundant neurotoxins in the environment. Despite the extensive movement made to eradicate toxic levels of Pb in the environment, children, predominately in lower socioeconomic areas, are still exposed to varying levels of Pb. Human studies suggest that Pb exposure leads to altered drug consumption in adults by altering underlying neural mechanisms, specifically dopamine (DA) activity. However, there is limited research on this at blood Pb levels below 10 μg/dL, levels often seen in children growing up in neighborhoods located in old industrial and urban areas. To model how early-life low-level Pb exposure effects DA-dependent behaviors associated with addiction in adulthood, we used C57BL/6J mice. Litters were weaned at PND 21 and assigned to either a three-week history of 30 parts per million (ppm) Lead (IV) Acetate exposure or a control condition of 0 ppm Pb in DI drinking water. After the Pb exposure period, mice were switched to regular tap water until they reached adulthood. Afterward, separate animals were tested in one of three experiments: two-bottle choice alcohol preference drinking, alcohol-induced behavioral sensitization (EBS), and cocaine-induced behavioral sensitization (CBS). In experiment 1, our hypothesis was met, and both male and female mice with a prior Pb exposure displayed significantly higher alcohol intake and preference scores over the three-week period than control mice. In experiment 2, there were no differences in EBS and no evidence of EBS in any of the groups. However, there was an increased acute response to 2.0 g/kg EtOH in the Pb-exposed chronic group as compared to the control animals. Lastly, in experiment 3, Pb-exposed animals in the chronic cocaine group were more sensitive to the effects of cocaine (10 mg/kg) across days than the controls, both the acute cocaine groups and both saline control groups. Thus, with these experiments, we concluded that low levels of developmental Pb exposure might be targeting DA in the reward pathway, which is essential for alcohol intake and drug sensitization.Item The Effects of Early-Life Lead Exposure on Adult Delta9-Tetrahydrocannabinol Sensitivity, Self-administration, and Tolerance(2022-08) Garcy, Daniel; Boehm, Stephen; Lapish, Christopher; Logrip, MarianEnvironmental exposure to lead (Pb) and cannabis use are two of the largest public health issues facing modern society in the United States and around the world. Exposure to Pb in early life has been unequivocally shown to have negative impacts on development, and recent research is mounting showing that it may also predispose individuals for risk of developing substance use disorders (SUD). At the same time, societal and legal attitudes towards cannabis (main psychoactive component delta-9-tetrahydrocannabinol) have been shifting, and many American states have legalized the recreational use of cannabis. It is also the 3rd most widely used drug of abuse in the US, and rates of cannabis use disorder are on the rise. This thesis sets out to establish whether there is a link between early life Pb exposure and later THC-related behavior in C57BL6/J mice, as has been demonstrated for other drugs of abuse. The first aim seeks to answer whether Pb exposure affects physiological THC sensitivity (as measured by the cannabinoid-induced tetrad). The second aim seeks to answer whether Pb exposure affects edible THC self-administration and the development of THC tolerance (also measured by the tetrad). It was hypothesized that Pb exposure would decrease THC sensitivity (Aim 1), would enhance THC self-administration (Aim 2), enhance the development of THC tolerance (Aim 2), and finally that sex-dependent effects of Pb-exposure and THC would be observed (Aims 1 & 2). These hypotheses ended up not being supported, but Aim 1 produced findings indicating that THC sensitivity was increased by Pb exposure, but only in female mice. Future research will hopefully be able to fully explore the implications of these findings.Item Examining Simultaneous Alcohol and ∆9-Tetrahydrocannabinol Self-Administration on Behavioral Flexibility and Dorsal Striatal CB1 Expression in cHAP Mice(2020-08) Millie, Lauren A.; Grahame, Nicholas; Boehm, Stephen; Logrip, Marian; Mackie, KenAlthough marijuana and alcohol are two of the most commonly used drugs in the United States, relatively little is understood about how these drugs interact to effect drug use, cognitive behaviors, and neurophysiological changes. Specific drug use patterns such as simultaneous use may produce differential effects for consumption and other behaviors in addition to unique neurobiological changes compared to singular drug use. In order to better understand the effects of simultaneous alcohol and marijuana (SAM) use, we used the selectively bred crossed High Alcohol Preferring mice to examine consummatory, cognitive, and neurobiological changes following chronic alcohol and THC self-administration. We hypothesized that SAM mice would consume more drug than animals exposed to either substance alone. We used an operant behavioral flexibility paradigm to assess cognitive impairments believing that drug-exposed animals would show deficits relative to Control animals, with SAM mice being the most impaired of all drug conditions. Finally, we assessed CB1 receptor changes in the dorsal striatum, as this region is critical for behavioral flexibility (Bissonette & Powell, 2012; Ragozzino, 2007), CB1 receptors are the primary target of THC and these receptors are involved in numerous alcohol related behaviors (Maldonado et al., 2006; Pava & Woodward, 2012). Contrary to our hypothesis, SAM animals did not consume higher levels of drug compared to mice exposed to only THC or alcohol. Interestingly, female THC consumption was robust when THC was consumed alone but was reduced when simultaneous access to alcohol was available. Surprisingly, although we speculated that drug-exposed mice would be impaired compared to Control animals, and that SAM animals would likely be more compromised than THC and alcohol for Reversal Learning and Attentional Set-Shifting respectively, behavioral flexibility deficits were absent in our paradigm. Finally, alterations to dorsal striatal CB1 receptor expression were observed following a Short Abstinence period. Despite an absence of cognitive behavioral effects, this research contributes to furthering our understanding of co-drug use for consummatory and neurobiological changes, both of which are critically necessary given the evolving landscape surrounding simultaneous alcohol and recreational marijuana use.Item Intra-nucleus accumbens shell injections of R(+)- and S(-)- baclofen bidirectionally alter binge-like ethanol, but not saccharin, intake in C57Bl/6J mice(Behavioural Brain Research (Elsevier), 2014) Kasten, Chelsea Rae; Czachowski, Cristine; Boehm, Stephen; Neal-Beliveau, Bethany S.; Grahame, Nicholas J.It has been proposed that the GABAB receptor subtype plays a role in alcoholism and alcohol use disorders (AUDs) (Cousins et al., 2002; Agabio et al., 2012). Specifically, the GABAB agonist baclofen has been looked at extensively in clinical and pre-clinical studies. In various animal models of chronic and intermittent consumption, baclofen has been shown to both increase (Petry, 1997; Smith et al., 1999; Czachowski et al., 2006; Moore et al., 2007) and decrease (Colombo et al., 2000; 2002; 2005; Stromberg, 2004; Moore et al., 2009) drinking. A critical issue in determining pharmacological effects of a drug is using the appropriate animal model. The drinking-in-the-dark (DID) model, developed by Rhodes et al. (2005, 2007), produces high levels of drinking in a binge-like paradigm and has been used to assess many pharmacological targets (e.g. Kamdar et al., 2007; Gupta et al., 2008; Moore et al., 2007; 2009). While DID produces high-levels of binge drinking, it is unclear what areas of the brain are involved in this behavior. A direct way to target areas that are believed to be involved in the circuitry of particular behaviors is through microinjection of drugs (Kiianmaa et al., 2003). Of particular recent interest involving motivated behaviors and addiction is the nucleus accumbens (Acb) (Everitt & Robbins, 2005); specifically the accumbens shell (AcbSh) (e.g. Rewal et al., 2009, 2012; Nie et al., 2011; Leriche et al., 2008). The current study aimed to investigate the role of GABAB receptors in the AcbSh by examining the ability of two different enantiomers of baclofen to alter ethanol and saccharin intake in male C57BL/6J (B6) mice. B6 mice underwent bilateral cannulation surgery targeting the AcbSh. After 48 hours of recovery time, animals began a five day Drinking-in-the-Dark (DID) procedure where they received 20% ethanol or 0.2% saccharin for two hours, three hours into the dark cycle, each day. Throughout the five drinking sessions, animals were kept in home-cage locomotor activity chambers to monitor activity throughout the drinking cycle. Day 4 drinking was immediately preceded by a mock microinjection, whereas Day 5 drinking was immediately preceded by a drug microinjection. Microinjection of one of five doses of baclofen was given in ng/side dissolved in 200 µl of aCSF (aCSF alone, 0.02 R(+)-, 0.04 R(+)-, 0.08 S(-)-, or 0,16 S(-)-). Intake was recorded every twenty minutes on Days 4 and 5. Retro-orbital sinus blood samples were taken from ethanol animals immediately following the Day 5 drinking period to determine blood ethanol concentrations (BECs). A one-way ANOVA on total Day 4 ethanol consumption revealed no baseline differences between dose groups. A one-way ANOVA on total Day 5 ethanol consumption revealed that the 0.04 R(+)- baclofen dose reduced total drinking, but the 0.16 S(-)- baclofen dose increased total drinking (p’s<0.05). This pattern was reflected in the BECs; 0.04 R(+)- baclofen reduced BECs, whereas 0.16 S(-)- baclofen increased BECs (p’s<0.05). These results were also time-dependent, with R(+)-baclofen reducing drinking in the first 20 minutes of the session and S(-)- increasing drinking in the last 40 minutes of the session. There were no effects on saccharin intake. An issue with the locomotor activity boxes led to unreliable locomotor activity counts. However, because there were no drug effects on saccharin consumption, it was concluded that locomotor effects did not contribute to the decreases or increases in ethanol consumption. These results further implicate the role of GABAB receptors in modulating ethanol intake. The bidirectional effects shown highlight the importance of considering enantioselective drug effects when interpreting data. Finally, these results also support previous conclusions that the AcbSh plays an important role in modulating use of drugs of abuse, but not other reinforcers.Item Investigating reactivity to incentive downshift as a correlated response to selection for high alcohol preference and a determinant of rash action and alcohol consumption(2014) Matson, Liana M.; Grahame, Nicholas J.; Czachowski, Cristine; Boehm, Stephen; Cyders, Melissa A.; Chester, Julia A.Losing a job or a significant other are examples of incentive shifts that result in negative emotional reactions. The occurrence of negative life events is associated with increased drinking, and alleviation of negative emotions has been cited as a drinking motive for individuals with problematic drinking patterns (Keyes et al., 2011; Adams et al., 2012). Further, there is evidence that certain genotypes drink alcohol in response to stressful negative life events (Blomeyer et al., 2008; Covault et al., 2007). It is possible that shared genetic factors contribute to both alcohol drinking and emotional reactivity, but there is a critical need for this relationship to be understood. The first aim of this proposal will use an incentive downshift paradigm to address whether emotional reactivity is elevated in mice predisposed to drink alcohol. The second aim of this proposal will address if reactivity to an incentive shift can result in rash action using a differential reinforcement of low rates of responding task, and whether this response is also associated with a predisposition for high drinking. The third aim of this proposal will investigate if experimenter administered ethanol reduces contrast effects, and if an incentive shift increases ethanol consumption in a high drinking line. The overall goal of this proposal is to investigate whether reactivity to incentive shift is an important mechanism underlying alcohol drinking in these mice, and the role an incentive shift may play in producing rash action and influencing ethanol consumption.Item Investigating the Modulation of Voltage-Gated Sodium Channel Nav1.1 Neuronal Excitability by Fibroblast Growth Factor Homologous Factor 2 and Il-6(2023-12) Frazee, Ashley; Cummins, Theodore; Berbari, Nicolas; Baucum, A.J.; Boehm, StephenMigraine is a condition that has affected many for generations and yet remains poorly understood. Mutations to the Nav1.1 voltage gated sodium channels have been implicated in various diseases such as Familial Hemiplegic Migraine 3 (FHM3), epilepsy, and autism spectrum disorder (ASD). Various proteins have been found to modify the function of these channels. Fibroblast growth factor homologous factors (FHFs) have been found to regulate the activity of some voltage-gated sodium channels (Navs). More work is needed to determine which FHFs affect which Navs. Here I looked at FHF2A and FHF2B in Nav1.1 as well as an FHM3-causing mutation to this channel, F1774S. I found that FHF2A, but not 2B, induced long-term inactivation (LTI) in the wild-type (WT) Nav1.1 and that FHF2A induced LTI in the F1774S mutant channel to a greater extent. Several changes in channel function caused by the mutation were attenuated with the addition of FHF2A, including persistent currents, leading to a possible rescue in the mutant phenotype. By contrast, the P1894L mutation, which has been found to cause ASD, greatly attenuated LTI and other impacts of FHF2A on Nav1.1. The inflammatory cytokine IL-6 was also investigated as a possible modulator of the Nav1.1 channel. There does not appear to be any direct interaction between this cytokine and the channel. Overall, my data shows for the first time that FHF2A, but FHF2B or IL-6, might be a significant modulator of Nav1.1 and can differentially modulate disease mutations.Item Investigating the role of extrasynaptic GABAA receptors located in the infralimbic cortex in the binge-like alcohol intake of male C57BL/6J mice(2013-11-20) Fritz, Brandon Michael; Boehm, Stephen; Czachowsk, Cristine; Grahame, Nicholas J.Extrasynaptic GABAA receptors, often identified as those containing both α4 and δ subunits, appear to be a target for the actions of alcohol (ethanol) at relatively low concentrations, perhaps suppressing the activity of GABAergic interneurons which regulate activity in the mesolimbocortical circuit. Pharmacological studies in rodents using the δ-subunit selective agonist Gaboxadol (THIP) have found both promotional and inhibitory effects on alcohol consumption. The goal of this project was to determine the role of extrasynaptic GABAA receptors located in the infralimbic cortex (ILC) in the binge-like alcohol intake of male C57BL/6J (B6) mice. The ILC is of interest due to its demonstrated involvement in stress reactivity and alcohol exposure has been shown to interfere with extinction learning; impairments of which may be related to inflexible behavior (i.e. problematic alcohol consumption). Adult male B6 mice were bilaterally implanted with stainless steel guide cannulae aimed at the ILC and were offered limited access to 20% ethanol or 5% sucrose for 6 days. On day 7, mice were bilaterally injected with 50 or 100 ng THIP (25 or 50 ng per side respectively) or saline vehicle into the ILC. It was found that the highest dose of THIP (100 ng/mouse) increased alcohol intake relative to vehicle controls, although control animals consumed relatively little ethanol following infusion. Furthermore, THIP had no effect on sucrose consumption (p > 0.05), suggesting that the effect of THIP was selective for ethanol consumption. Together, these findings suggest that the mice that consumed ethanol may have been particularly reactive to the microinfusion process relative to animals that consumed sucrose, perhaps because ethanol consumption was not as reinforcing as sucrose consumption. In addition, the observation that THIP effectively prevented the decrease in ethanol intake on day 7 induced by the microinjection process may be related to a role for the ILC in adaptive learning processes, which in turn, promote behavioral flexibility.Item Modelling Nicotine Self-Administration Using Drinking-in-the-Dark(Office of the Vice Chancellor for Research, 2015-04-17) Frazee, Ashley; Kasten, Chelsea; Boehm, StephenAlthough cigarette smoking is a widely recognized problem in the United States, few animal models of nicotine self-administration exist. One aim of this study was to develop a new model of nicotine selfadministration in animals. The Drinking in Dark (DID) model, in which ethanol access is given for two hours, three hours into the dark cycle, can be easily altered to investigate nicotine intake and withdrawal. We found that animals will readily consume around 6 mg/kg of nicotine per day, which is equivalent to smoking approximately 3-4 cigarettes. A second aim of the study was to test pharmacological manipulations in the model. Two areas of focus for pharmaceutical manipulations involve GABA and acetylcholine. On the fifth day of nicotine DID we administered baclofen, a GABAB receptor agonist, or mecamylamine, a nicotinic acetylcholine receptor (nAChR) antagonist, immediately prior to nicotine consumption. We found that baclofen, but not mecamylamine, reduced nicotine intake (p < .05). The final aim of the study will be to test for face validity of the model. A separate group of mice will be given access to nicotine or saccharin for 5 or 10 days using DID procedures. Face validity of the model will be tested using the elevated plus maze and by observing locomotor activity during spontaneous withdrawal, approximately 55 hours following the last DID presentation. Taken together, these studies suggest that nicotine DID is a valid model of voluntary nicotine intake that can be tested for smoking treatments, as well as the neurobiological underpinnings of repeated nicotine use.