Browsing by Subject "C57BL/6J"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    Activation of extrasynaptic δ-GABAA receptors globally or within the posterior-VTA has estrous-dependent effects on consumption of alcohol and estrous-independent effects on locomotion
    (Elsevier, 2017-09) Melón, Laverne C.; Nolan, Zachary T.; Colar, Delphine; Moore, Eileen M.; Boehm II, Stephen L.; Psychology, School of Science
    Recent reports support higher than expected rates of binge alcohol consumption among women and girls. Unfortunately, few studies have assessed the mechanisms underlying this pattern of intake in females. Studies in males suggest that alcohol concentrations relevant to the beginning stages of binge intoxication may selectively target tonic GABAergic inhibition mediated by GABAA receptor subtypes expressing the δ-subunit protein (δ-GABAARs). Indeed, administration of agonists that interact with these δ-GABAARs prior to alcohol access can abolish binge drinking behavior in male mice. These δ-GABAARs have also been shown to exhibit estrous-dependent plasticity in regions relevant to drug taking behavior, like the hippocampus and periaqueductal gray. The present experiments were designed to determine whether the estrous cycle would alter binge drinking, or our ability to modulate this pattern of alcohol use with THIP, an agonist with high selectivity and efficacy at δ-GABAARs. Using the Drinking-in-the-Dark (DID) binge-drinking model, regularly cycling female mice were given 2h of daily access to alcohol (20%v/v). Vaginal cytology or vaginal impedance was assessed after drinking sessions to track estrous status. There was no fluctuation in binge drinking associated with the estrous cycle. Both Intra-posterior-VTA administration of THIP and systemic administration of the drug was also associated with an estrous cycle dependent reduction in drinking behavior. Pre-treatment with finasteride to inhibit synthesis of 5α-reduced neurosteroids did not disrupt THIP's effects. Analysis of δ-subunit mRNA from posterior-VTA enriched tissue samples revealed that expression of this GABAA receptor subunit is elevated during diestrus in this region. Taken together, these studies demonstrate that δGABAARs in the VTA are an important target for binge drinking in females and confirm that the estrous cycle is an important moderator of the pharmacology of this GABAA receptor subtype.
  • Thumbnail Image
    Item
    Divergent compensatory responses to high-fat diet between C57BL6/J and C57BLKS/J inbred mouse strains
    (American Physiological Society (APS), 2013-12-15) Sims, Emily K.; Hatanaka, Masayuki; Morris, David L.; Tersey, Sarah A.; Kono, Tatsuyoshi; Chaudry, Zunaira Z.; Day, Kathleen H.; Moss, Dan R.; Stull, Natalie D.; Mirmira, Raghavendra G.; Evans-Molina, Carmella; Department of Medicine, IU School of Medicine
    Impaired glucose tolerance (IGT) and type 2 diabetes (T2DM) are polygenic disorders with complex pathophysiologies; recapitulating them with mouse models is challenging. Despite 70% genetic homology, C57BL/6J (BL6) and C57BLKS/J (BLKS) inbred mouse strains differ in response to diet- and genetic-induced obesity. We hypothesized these differences would yield insight into IGT and T2DM susceptibility and response to pharmacological therapies. To this end, male 8-wk-old BL6 and BLKS mice were fed normal chow (18% kcal from fat), high-fat diet (HFD; 42% kcal from fat), or HFD supplemented with the PPARγ agonist pioglitazone (PIO; 140 mg PIO/kg diet) for 16 wk. Assessments of body composition, glucose homeostasis, insulin production, and energy metabolism, as well as histological analyses of pancreata were undertaken. BL6 mice gained weight and adiposity in response to HFD, leading to peripheral insulin resistance that was met with increased β-cell proliferation and insulin production. By contrast, BLKS mice responded to HFD by restricting food intake and increasing activity. These behavioral responses limited weight gain and protected against HFD-induced glucose intolerance, which in this strain was primarily due to β-cell dysfunction. PIO treatment did not affect HFD-induced weight gain in BL6 mice, and decreased visceral fat mass, whereas in BLKS mice PIO increased total fat mass without improving visceral fat mass. Differences in these responses to HFD and effects of PIO reflect divergent human responses to a Western lifestyle and underscore the careful consideration needed when choosing mouse models of diet-induced obesity and diabetes treatment.
  • Thumbnail Image
    Item
    Effect 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.