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Item Chronic free-choice drinking in crossed HAP (cHAP) mice leads to sustained blood ethanol levels and metabolic tolerance without evidence of liver damage(Wiley, 2013-02) Matson, Liana; Liangpunsakul, Suthat; Crabb, David; Buckingham, Amy; Ross, Ruth Ann; Halcomb, Meredith; Grahame, Nicholas; Department of Psychology, School of ScienceBackground Crossed High Alcohol Preferring (cHAP) mice were selectively bred from a cross of the HAP1xHAP2 replicate lines, and demonstrate blood ethanol concentrations (BECs) during free-choice drinking that are reminiscent of those observed in alcohol-dependent humans. Therefore, this line may provide an unprecedented opportunity to learn about the consequences of excessive voluntary ethanol consumption, including metabolic tolerance and liver pathology. Cytochrome p450 2E1 (CYP 2E1) induction plays a prominent role in driving both metabolic tolerance and ethanol-induced liver injury. In this report, we sought to characterize cHAP drinking by assessing whether pharmacologically relevant BEC levels are sustained throughout the active portion of the light-dark cycle. Given that cHAP intakes and BECs are similar to those observed in mice given an ethanol liquid diet, we assessed whether free-choice exposure results in metabolic tolerance, hepatic enzyme induction, and hepatic steatosis. Methods In Experiment 1, blood samples were taken across the dark portion of a 12:12 light-dark cycle to examine the pattern of ethanol accumulation in these mice. In Experiments 1 and 2, mice were injected with ethanol following 3–4 weeks of access to water or 10% ethanol and water, and blood samples were taken to assess metabolic tolerance. In Experiment 3, 24 mice had 4 weeks access to 10% ethanol and water or water alone, followed by necropsy and hepatological assessment. Results In experiment 1, cHAP mice mean BEC values exceeded 80 mg/dl at all sampling points, and approached 200 mg/dl during the middle of the dark cycle. In experiments 1 and 2, ethanol-exposed mice metabolized ethanol faster than ethanol-naïve mice, demonstrating metabolic tolerance (p < .05). In experiment 3, ethanol-drinking mice showed greater expression of hepatic CYP 2E1 than water controls, consistent with the development of metabolic tolerance (p < .05). Ethanol access altered neither hepatic histology nor levels of ADH and ALDH. Conclusions These results demonstrate that excessive intake by cHAP mice results in sustained BECs throughout the active period, leading to the development of metabolic tolerance and evidence of CYP 2E1 induction. Together these results provide additional support for the cHAP mice as a highly translational rodent model of alcoholism.Item Habit Formation: Implications for Alcoholism Research(Elsevier B.V., 2014-06) O’Tousa, David; Grahame, Nicholas; Department of Psychology, School of ScienceCharacteristics of individuals with severe alcohol use disorders include heightened cue sensitivity, compulsive seeking, craving, and continued alcohol use in the face of negative consequences. Animal models are useful for understanding behavioral and neurological mechanisms underlying problematic alcohol use. Seeking of operant reinforcers including alcohol is processed by two mechanisms, commonly referred to as “goal-directed” (action-outcome) and “habitual” (stimulus-response). As substance use disorders are characterized by continued use regardless of unfavorable outcomes, it is plausible that drug use causes an unnatural disruption of these mechanisms. We present a critical analysis of literature pertaining to behavioral neuroscience alcoholism research involving habit formation. Traditionally, when operant behavior is unaffected by a loss of subjective value of a reinforcer (devaluation), the behavior is considered habitual. Acquisition of instrumental behavior requires corticostriatal mechanisms that depend heavily on the prefrontal cortex and ventral striatum, whereas practiced behavior is more predominantly controlled by the dorsal striatum. Dopaminergic signaling is necessary for the neurological adaptations involved in stimulus-response action, and drugs of abuse appear to facilitate habitual behavior through high levels of dopamine release. Evidence suggests that the use of alcohol as a reinforcer expedites habit formation, and that a history of alcohol use produces alterations in striatal morphology, aids habit learning for non-psychoactive reinforcers, and promotes alcohol drinking despite aversive adulterants. In this review, we suggest directions for future alcoholism research that seeks to measure action made despite a devalued outcome, including procedural modifications and genotypic, pharmacological, or neurological manipulations. Most alcoholism models currently in use fail to reach substantial blood ethanol concentrations, a shortcoming that may be alleviated through the use of high-drinking rodent lines. Additionally, satiety, one common mechanism of devaluing reinforcers, is not recommended for alcohol research because the psychoactive effects of alcohol depress response rates, mimicking devaluation effects. Overall, further research of habit formation and potentially related perseverative behaviors could be invaluable in discovering genetic variance, traits that correlate with persistent alcohol seeking, implicated neural structures and processes of alcohol use, and eventually novel pharmacological treatment for alcoholism.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.Item Self-administration of edible Δ9-tetrahydrocannabinol and associated behavioral effects in mice(Elsevier, 2019) Smoker, Michael P.; Mackie, Ken; Lapish, Christopher C.; Boehm, Stephen L., II; Psychology, School of ScienceBackground With increasing access to legal cannabis across the globe, it is imperative to more closely study its behavioral and physiological effects. Furthermore, with the proliferation of cannabis use, modes of consumption are changing, with edible formulations becoming increasingly popular. Nevertheless, there are relatively few animal models of self-administration of the primary psychoactive component of cannabis, Δ9-tetrahydrocannabinol (THC), and almost all incorporate routes of administration other than those used by humans. The aim of the current study was to develop a model of edible THC self-administration and assess its impact on CB1 receptor-mediated behaviors in female and male mice. Methods Mice were given limited access to a palatable dough which occasionally contained THC in doses ranging from 1 to 10 mg/kg. Following dough consumption, mice were assessed for home cage locomotor activity, body temperature, or analgesia. Locomotor activity was also assessed in conjunction with the CB1 receptor antagonist SR141716A. Results Dough was well-consumed, but consumption decreased at the highest THC concentrations. Edible THC produced dose-dependent decreases in locomotor activity and body temperature in both sexes, and these effects were more pronounced in male mice. Hypolocomotion induced by edible THC was attenuated by SR141716A, indicating mediation by CB1 receptor activation. Conclusions In contrast to other cannabinoid self-administration models, edible THC is relatively low in stress and uses a route of administration analogous to one used by humans. Potential applications include chronic THC self-administration, determining THC reward/reinforcement, and investigating consequences of oral THC use.