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ItemAssessment 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. ItemDetermination of the Rewarding Capacity of Edible and Injected Delta-9-Tetrahydrocannabinol in Adolescent and Adult Mice(2020-05) Smoker, Michael P.; Lapish, Christopher C.; Boehm II, Stephen L.; Goodlett, Charles R.; Mackie, Kenneth P.Cannabis (and its main psychoactive component, THC) is one of the most widely-used drugs in the world, and recent expansion of its legal status has made it available in a variety of formulations and at a potency unrivaled in history. While its medicinal properties are gaining scientific support, so too is its potential to lead to abuse and dependence. Both initiation of cannabis use and frequent cannabis use are most prevalent in adolescence, and compared to adults, cannabis use by adolescents is associated with a greater likelihood of developing cannabis dependence and cannabis use disorder. Given the ethical limitations surrounding research that provides cannabis to non-users or non-adults, animal models of drug use can be valuable tools for the study of causes and consequences related to drug use, as well as allowing for investigating brain mechanisms underlying these factors. However, only recently have models in which animals reliably use cannabis (THC) at levels above its respective vehicle and at levels which produce consistent behavioral and physiological effects become available, and in no case has age-related differences in this use been examined. Thus, one goal of the current study was to directly compare the self-administration of edible THC (a route of administration used by humans and a formulation increasing in popularity) between adolescent and adult mice. Adolescents also appear to be differentially sensitive to various effects of several classes of drugs, and they have been shown to be less sensitive to the aversive effects of cannabis, thereby putting them at greater risk for elevated and continued use. Evidence also suggests that, in addition to the risk associated with adolescent cannabis use, having initial positive subjective experiences resulting from its use is a strong predictor of subsequent cannabis dependence. Thus, the second goal of the current study was to use the place conditioning paradigm to examine the reward- (or aversion-) inducing properties of THC in adolescent and adult C57BL/6J mice, using both the traditional experimenter-administered THC (via injection) as well as edible THC self-administration. Prior to initiating these THC studies, sensitivity of the place conditioning procedure to age-related differences in drug-induced reward was validated using cocaine, yielding locomotor stimulation in both ages and a decreased sensitivity to cocaine’s rewarding properties in adolescent mice. When provided limited access to edible THC dough in doses ranging from 0.0 to 6.0 mg/kg, mice showed a dose-dependent reduction in consumption across access sessions, and this reduction was more rapid in adult mice at the highest doses, suggesting that adolescent mice might have been less sensitive to its aversive properties. These same mice, as well as a separate group of mice receiving injection (also 0.0 to 6.0 mg/kg THC), were given place conditioning sessions, alternating between THC dough and control dough or THC injection and vehicle injection, for 6 days per week and were tested once per week across a total of 3 weeks. Mice conditioned using edible THC showed a neutral response (neither reward nor aversion) at all doses. However, mice conditioned using injected THC showed a conditioned place aversion to the highest dose, which was more pronounced in adult mice. Interestingly, in mice self-administering edible THC, the dose of THC consumed was related to the outcome of place conditioning, such that a conditioned place preference was observed for adult mice which shifted their consumption of 3.0 mg/kg edible THC downward relative to those mice with full consumption of 3.0 mg/kg, and for adolescent mice which had the highest degree of consumption of 6.0 mg/kg edible THC relative to those mice with the lowest consumption of 6.0 mg/kg. Furthermore, initial place preference outcomes at the individual level at test 1 predicted subsequent doses of edible THC consumed, suggesting mice adjust their self-administration of edible THC based on the subjective experience it produces. Besides its impact in place conditioning, THC also had differential effects on body weight and locomotor activity based on age and route of administration. Collectively, this project demonstrates that adolescent mice are less sensitive to the hedonic properties of both cocaine and THC, and that differences in edible THC self-administration between ages, and between individuals within an age, are likely related the subjective experience of its rewarding and aversive properties. ItemDevelopment of a computerized adaptive substance use disorder scale for screening, measurement and diagnosis - The CAT-SUD-E(Elsevier, 2022-03-23) Hulvershorn, Leslie A.; Adams, Zachary W.; Smoker, Michael P.; Aalsma, Matthew C.; Gibbons, Robert D.; Psychiatry, School of MedicineIntroduction: The Computerized Adaptive Test for Substance Use Disorder (CAT-SUD), an adaptive test based on multidimensional item response theory, has been expanded to include 7 specific Diagnostic and Statistical Manual, 5th edition (DSM-5) defined SUDs. Initial testing of the new measure, the CAT-SUD expanded (CAT-SUD-E) is reported here. Methods: 275 Community-dwelling adults (ages 18-68) responded to public and social-media advertisements. Participants virtually completed both the CAT-SUD-E and the Structured Clinical Interview for DSM-5, Research Version (SCID) to assess the validity of the CAT-SUD-E in determining whether participants met criteria for specific DSM-5 SUDs. Diagnostic classifications were based on 7 SUDs, each with 5 items, for current and lifetime SUDs. Results: For SCID-based presence of any lifetime SUD, predictions based on the overall CAT-SUD-E diagnosis and severity score were AUC=0.92, 95% CI = 0.88, 0.95 for current and AUC=0.94, 95% CI = 0.91, 0.97 for lifetime. For individual diagnoses, classification accuracy for current SUDs ranged from an AUC=0.76 for alcohol to AUC=0.92 for nicotine/tobacco. Classification accuracy for lifetime SUDs ranged from an AUC=0.81 for hallucinogens to AUC=0.96 for stimulants. Median CAT-SUD-E completion time was under 4 min. Conclusions: The CAT-SUD-E quickly produces similar results as lengthy structured clinical interviews for overall SUD and substance-specific SUDs, with high precision and accuracy, through a combination of fixed-item responses for diagnostic classification and adaptive SUD severity measurement. The CAT-SUD-E harmonizes information from mental health, trauma, social support and traditional SUD items to provide a more complete characterization of SUD and provides both diagnostic classification and severity measurement. ItemEffect of GABRA2 expression in the central nucleus of the amygdala on anxiety and alcohol's anxiolytic capacity in C57BL/6J mice(2016) Smoker, Michael P.; Boehm, Stephen L.; Lapish, Christopher C.; Czachowski, Cristine Lynn; Grahame, Nicholas J.The GABRA2 gene, which encodes the α2 subunit of GABAA receptors, is one of the genes most frequently associated with alcohol-related behavior in human studies (Demers, Bogdan, & Agrawal, 2014). Polymorphisms in GABRA2 have been found to be associated with alcohol dependence, changes in drinking frequency, and alcohol’s stimulating and euphoric effects (Arias et al., 2014; Dick et al., 2014; Edenberg et al., 2004). However, the GABRA2-alcohol relationship may not be direct, as anxiety and impulsiveness have been found to be mediating factors (Enoch, Schwartz, Albaugh, Virkkunen, & Goldman, 2006; Villafuerte, Strumba, Stoltenberg, Zucker, & Burmeister, 2013). Comorbidity of anxiety and alcohol use disorders is both prevalent and clinically relevant (J. P. Smith & Randall, 2012), and GABAA receptors play a significant role in each. Benzodiazepines, primary pharmacologic treatments for anxiety disorders and alcohol withdrawal, facilitate signaling at GABAA receptors, and their anxiolytic effects appear to depend on the presence of α2 subunits in these receptors (Low et al., 2000). The amygdala is widely implicated in both anxiety disorders as well as addiction (Janak & Tye, 2015), and its central nucleus is an important mediator of responses to both alcohol- and stress-related stimuli (Roberto, Gilpin, & Siggins, 2012), some of which may be related to GABRA2 expression within this region (Jin et al., 2014). The aim of the current study was to explore the role of Gabra2 (mouse ortholog of GABRA2) expression within the central nucleus of the amygdala (CeA) in anxiety-related behavior and alcohol’s anxiolytic effects in mice. C57BL/6J (B6) mice underwent surgery for bilateral infusion of GFP-tagged lentivirus targeting Gabra2 or a scramble control lentivirus into the CeA. Following 12-13 days of recovery, mice were assessed for anxiety-like behavior in the elevated plus maze (EPM) naïve or following IP injection of 0, 0.75, or 1.5 g/kg ethanol. After assessment, brains were extracted and sectioned through the CeA. Finally, GFP was quantified, the CeA was collected via laser microdissection, and α2 protein was quantified via ELISA. In mice expressing GFP in the CeA, α2 protein concentrations were lower for Virus mice relative to Control mice. The EPM was anxiogenic, and alcohol was found to be anxiolytic. In naïve mice, while there was no difference between Control mice and Virus mice on any behavioral measure, there were significant correlations between CeA α2 protein concentration and time spent in closed arms as well as both total and average time spent in open arms. In mice receiving injection of 0, 0.75, or 1.5 g/kg ethanol, there was a main effect of dose on several behavioral measures, but no interaction between viral condition and dose, and only a main effect of viral condition on average time spent in closed arms. There were no significant correlations between CeA α2 protein concentration and behavioral measures within any injected dose. These results are consistent with GABRA2-anxiety associations and effects of Gabra2 manipulation on anxiety-like behavior. Furthermore, they suggest that CeA α2 protein concentration is positively related to basal anxiety, which could affect alcohol use through various routes. However, these results also suggest that CeA α2 protein concentration is not related to alcohol’s anxiolytic capacity, at least when acutely administered in alcohol-naïve animals. ItemEvidence-based Treatment for Substance Use Disorders in Community Mental Health Centers: the ACCESS Program(Springer Nature, 2023) Aalsma, Matthew C.; Adams, Zachary W.; Smoker, Michael P.; Marriott, Brigid R.; Ouyang, Fangqian; Meudt, Emily; Hulvershorn, Leslie A.; Pediatrics, School of MedicineA significant gap remains in the availability and accessibility of evidence-based treatments (EBTs) in community substance use disorder (SUD) treatment. This study describes a 2-year statewide training initiative that sought to address this gap by training community-based therapists in motivational enhancement/cognitive behavioral therapy (MET/CBT). Therapists (N = 93) participated in a 2-day MET/CBT workshop followed by bi-weekly clinical consultation, fidelity monitoring, guided readings, and online resources. Therapists completed pre-training and follow-up assessments measuring knowledge, attitudes, confidence, and implementation barriers. Most therapists attended 10 or more consultation calls. Submission of session recordings for feedback was the least utilized training element. Therapists reported increased confidence in their ability to implement MET/CBT for SUD and demonstrated improvement in MI and CBT knowledge. Therapists reported several implementation barriers, including lack of time and opportunity to treat patients with MET/CBT. Recommendations for future training initiatives and addressing the barriers identified in this study are discussed. ItemImpulsivity in rodents with a genetic predisposition for excessive alcohol consumption is associated with a lack of a prospective strategy(Springer, 2017-04) Linsenbardt, David N.; Smoker, Michael P.; Janetsian-Fritz, Sarine S.; Lapish, Christopher C.; Psychology, School of ScienceIncreasing evidence supports the hypothesis that impulsive decision-making is a heritable risk factor for an alcohol use disorder (AUD). Clearly identifying a link between impulsivity and AUD risk, however, is complicated by the fact that both AUDs and impulsivity are heterogeneous constructs. Understanding the link between the two requires identifying the underlying cognitive factors that lead to impulsive choices. Rodent models have established that a family history of excessive drinking can lead to the expression of a transgenerational impulsive phenotype, suggesting heritable alterations in the decision-making process. In the present study, we explored the cognitive processes underlying impulsive choice in a validated, selectively bred rodent model of excessive drinking-the alcohol-preferring ("P") rat. Impulsivity was measured via delay discounting (DD), and P rats exhibited an impulsive phenotype as compared to their outbred foundation strain-Wistar rats. Steeper discounting in P rats was associated with a lack of a prospective behavioral strategy, which was observed in Wistar rats and was directly related to DD. To further explore the underlying cognitive factors mediating these observations, a drift diffusion model of DD was constructed. These simulations supported the hypothesis that prospective memory of the delayed reward guided choice decisions, slowed discounting, and optimized the fit of the model to the experimental data. Collectively, these data suggest that a deficit in forming or maintaining a prospective behavioral plan is a critical intermediary to delaying reward, and by extension, may underlie the inability to delay reward in those with increased AUD risk. ItemSelf-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. ItemTime-course of extracellular nicotine and cotinine levels in rat brain following administration of nicotine: effects of route and ethanol coadministration(Springer, 2015-02) Katner, Simon N.; Toalston, Jamie E.; Smoker, Michael P.; Rodd, Zachary A.; McBride, William J.; Engleman, Eric A.; Psychiatry, School of MedicineRATIONALE: Nicotine and ethanol are commonly coabused drugs, and nicotine-laced ethanol products are growing in popularity. However, little is known about time-course changes in extracellular nicotine and cotinine levels in rat models of ethanol and nicotine coabuse. OBJECTIVES: The objective of the present study was to determine the time-course changes in brain levels of nicotine and cotinine following subcutaneous (SC) and intragastric (IG) nicotine administration in alcohol-preferring (P) and Wistar rats. METHODS: In vivo microdialysis was used to collect dialysate samples from the nucleus accumbens shell (NACsh) for nicotine and cotinine determinations, following SC administration of (-)-nicotine (0.18, 0.35, and 0.70 mg/kg) in female P and Wistar rats or IG administration of (-)-nicotine (0.35 and 0.70 mg/kg) in 15 % (v/v) ethanol or water in female P rats. RESULTS: SC nicotine produced nicotine and cotinine dialysate levels as high as 51 and 14 ng/ml, respectively. IG administration of 15 % EtOH + 0.70 mg/kg nicotine in P rats resulted in maximal nicotine and cotinine dialysate levels of 19 and 14 ng/ml, respectively, whereas administration of 0.70 mg/kg nicotine in water resulted in maximal nicotine and cotinine levels of 21 and 25 ng/ml, respectively. Nicotine and cotinine levels were detectable within the first 15 and 45 min, respectively, after IG administration. CONCLUSIONS: Overall, the results of this study suggest that nicotine is rapidly adsorbed and produces relevant extracellular brain concentrations of nicotine and its pharmacologically active metabolite, cotinine. The persisting high brain concentrations of cotinine may contribute to nicotine addiction.