Browsing by Author "Hile, Karen L."

Now showing 1 - 5 of 5
  • Thumbnail Image
    Item
    Differences in IV alcohol-induced dopamine release in the ventral striatum of social drinkers and nontreatment-seeking alcoholics
    (Elsevier, 2016-03) Yoder, Karmen K.; Albrecht, Daniel S.; Dzemidzic, Mario; Normandin, Marc D.; Federici, Lauren M.; Graves, Tammy; Herring, Christine M.; Hile, Karen L.; Walters, James W.; Liang, Tiebing; Plawecki, Martin H.; O'Connor, Sean; Kareken, David A.; Department of Radiology and Imaging Sciences, IU School of Medicine
    Background Striatal dopamine (DA) has been implicated in alcohol use disorders, but it is still unclear whether or not alcohol can induce dopamine release in social drinkers. Furthermore, no data exist on dopamine responses to alcohol in dependent drinkers. We sought to characterize the DA responses to alcohol intoxication in moderately large samples of social drinkers (SD) and nontreatment-seeking alcoholics (NTS). Methods Twenty-four SD and twenty-one NTS received two [11C]raclopride (RAC) PET scans; one at rest, and one during an intravenous alcohol infusion, with a prescribed ascent to a target breath alcohol concentration (BrAC), at which it was then “clamped.” The alcohol clamp was started 5 min after scan start, with a linear increase in BrAC over 15 min to the target of 80 mg%, the legal threshold for intoxication. Target BrAC was maintained for 30 min. Voxel-wise binding potential (BPND) was estimated with MRTM2. Results IV EtOH induced significant increases in DA in the right ventral striatum in NTS, but not SD. No decreases in DA were observed in either group. Conclusions Alcohol intoxication results in distinct anatomic profiles of DA responses in SD and NTS, suggesting that in NTS, the striatal DA system may process effects of alcohol intoxication differently than in SD.
  • Thumbnail Image
    Item
    Effects of acute alcohol exposure and chronic alcohol use on neurite orientation dispersion and density imaging (NODDI) parameters
    (Springer, 2023) Yoder, Karmen K.; Chumin, Evgeny J.; Mustafi, Sourajit M.; Kolleck, Kelly A.; Halcomb, Meredith E.; Hile, Karen L.; Plawecki, Martin H.; O’Connor, Sean J.; Dzemidzic, Mario; Wu, Yu‑Chien; Radiology and Imaging Sciences, School of Medicine
    Rationale: Little is known about how acute and chronic alcohol exposure may alter the in vivo membrane properties of neurons. Objectives: We employed neurite orientation dispersion and density imaging (NODDI) to examine acute and chronic effects of alcohol exposure on neurite density. Methods: Twenty-one healthy social drinkers (CON) and thirteen nontreatment-seeking individuals with alcohol use disorder (AUD) underwent a baseline multi-shell diffusion magnetic resonance imaging (dMRI) scan. A subset (10 CON, 5 AUD) received dMRI during intravenous infusions of saline and alcohol during dMRI. NODDI parametric images included orientation dispersion (OD), isotropic volume fraction (ISOVF), and corrected intracellular volume fraction (cICVF). Diffusion tensor imaging metrics of fractional anisotropy and mean, axial, and radial diffusivity (FA, MD, AD, RD) were also computed. Average parameter values were extracted from white matter (WM) tracts defined by the Johns Hopkins University atlas. Results: There were group differences in FA, RD, MD, OD, and cICVF, primarily in the corpus callosum. Both saline and alcohol had effects on AD and cICVF in WM tracts proximal to the striatum, cingulate, and thalamus. This is the first work to indicate that acute fluid infusions may alter WM properties, which are conventionally believed to be insensitive to acute pharmacological challenges. It also suggests that the NODDI approach may be sensitive to transient changes in WM. The next steps should include determining if the effect on neurite density differs with solute or osmolality, or both, and translational studies to assess how alcohol and osmolality affect the efficiency of neurotransmission.
  • Thumbnail Image
    Item
    IL-18 Activation is Dependent on Toll Like Receptor 4 during Renal Obstruction
    (Elsevier, 2013) Rhee, Audrey C.; Cain, Alexandra L.; Hile, Karen L.; Zhang, Hongji; Matsui, Futoshi; Meldrum, Kirstan K.; Urology, School of Medicine
    Purpose: Interleukin 18 (IL-18) is a critical mediator of obstruction-induced renal injury. Although previous studies have demonstrated that IL-18 participates in a positive feedback loop via the IL-18 receptor (IL-18R) and localized renal IL-18 and IL-18R production to tubular epithelial cells (TEC), the mechanism of IL-18 activation during obstruction remains unclear. We hypothesized that IL-18 activation is dependent on Toll-like receptor 4 (TLR4) signaling during renal obstruction. Materials and methods: Male C57BL6 TLR4 knockout (TLR4KO) and wild-type (WT) mice were subjected to unilateral ureteral obstruction versus sham operation for 1 wk. The animals were sacrificed, and renal cortical tissue was harvested and analyzed for TLR4 expression (Western blot), active IL-18 production (enzyme-linked immunosorbent assay, real-time polymerase chain reaction), IL-18 receptor expression (real-time polymerase chain reaction), and TLR4/IL-18 versus IL-18R cellular localization (dual immunofluorescent staining). Results: Renal TLR4 expression increased significantly in WT mice in response to obstruction, but remained at sham treatment levels in TLR4KO mice. IL-18 and IL-18R gene expression and active IL-18 production were similarly increased in WT mice in response to obstruction, but decreased significantly to sham treatment levels in the absence of TLR4. Dual immunofluorescent staining revealed co-localization of TLR4 and IL-18 to renal TEC during obstruction. Conclusion: IL-18 production and activation during renal obstruction is dependent on intact TLR4 signaling. Co-localization of IL-18 and TLR4 production to TEC during obstruction suggests that TEC are the primary site of IL-18 production and activation. Further characterization of the pathway may be necessary to develop targeted therapy in obstruction-induced renal injury.
  • Thumbnail Image
    Item
    Mesenchymal stem cells protect against obstruction-induced renal fibrosis by decreasing STAT3 activation and STAT3-dependent MMP-9 production
    (American Physiological Society, 2017-01-01) Matsui, Futoshi; Babitz, Stephen A.; Rhee, Audrey; Hile, Karen L.; Zhang, Hongji; Meldrum, Kirstan K.; Urology, School of Medicine
    STAT3 is a transcription factor implicated in renal fibrotic injury, but the role of STAT3 in mesenchymal stem cell (MSC)-induced renoprotection during renal fibrosis remains unknown. We hypothesized that MSCs protect against obstruction-induced renal fibrosis by downregulating STAT3 activation and STAT3-induced matrix metalloproteinase-9 (MMP-9) expression. Male Sprague-Dawley rats underwent renal arterial injection of vehicle or MSCs (1 × 106/rat) immediately before sham operation or induction of unilateral ureteral obstruction (UUO). The kidneys were harvested after 4 wk and analyzed for collagen I and III gene expression, collagen deposition (Masson's trichrome), fibronectin, α-smooth muscle actin, active STAT3 (p-STAT3), MMP-9, and tissue inhibitor of matrix metalloproteinases 1 (TIMP-1) expression. In a separate arm, the STAT3 inhibitor S3I-201 (10 mg/kg) vs. vehicle was administered to rats intraperitoneally just after induction of UUO and daily for 14 days thereafter. The kidneys were harvested after 2 wk and analyzed for p-STAT3 and MMP-9 expression, and collagen and fibronectin deposition. Renal obstruction induced a significant increase in collagen, fibronectin, α-SMA, p-STAT3, MMP-9, and TIMP-1 expression while exogenously administered MSCs significantly reduced these indicators of obstruction-induced renal fibrosis. STAT3 inhibition with S3I-201 significantly reduced obstruction-induced MMP-9 expression and tubulointerstitial fibrosis. These results demonstrate that MSCs protect against obstruction-induced renal fibrosis, in part, by decreasing STAT3 activation and STAT3-dependent MMP-9 production.
  • Thumbnail Image
    Item
    Monetary discounting and ventral striatal dopamine receptor availability in nontreatment-seeking alcoholics and social drinkers
    (Springer-Verlag, 2015-06) Oberlin, Brandon G.; Albrecht, Daniel S.; Herring, Christine M.; Walters, James W.; Hile, Karen L.; Kareken, David A.; Yoder, Karmen K.; Department of Radiology and Imaging Sciences, IU School of Medicine
    RATIONALE: Dopamine (DA) in the ventral striatum (VST) has long been implicated in addiction pathologies, yet its role in temporal decision-making is not well-understood. OBJECTIVES: To determine if VST DA D2 receptor availability corresponds with greater impulsive choice in both nontreatment-seeking alcoholics (NTS) and social drinkers (SD). METHODS: NTS subjects (n = 10) and SD (n = 13) received PET scans at baseline with the D2/D3 radioligand [(11)C]raclopride (RAC). Outside the scanner, subjects performed a delay discounting procedure with monetary rewards. RAC binding potential (BPND) was estimated voxelwise, and correlations were performed to test for relationships between VST BPND and delay discounting performance. Self-reported impulsivity was also tested for correlations with BPND. RESULTS: Across all subjects, greater impulsive choice for $20 correlated with lower BPND in the right VST. NTS showed greater impulsive choice than SD and were more impulsive by self-report. Across all subjects, the capacity of larger rewards to reduce impulsive choice (the magnitude effect) correlated negatively (p = 0.028) with problematic alcohol use (AUDIT) scores. Self-reported impulsivity did not correlate with BPND in VST. CONCLUSIONS: Preference for immediate reinforcement may reflect greater endogenous striatal DA or lower D2 number, or both. Alcoholic status did not mediate significant effects on VST BPND, suggesting minimal effects from alcohol exposure. The apparent lack of BPND correlation with self-reported impulsivity highlights the need for objective behavioral assays in the study of the neurochemical substrates of behavior. Finally, our results suggest that the magnitude effect may be more sensitive to alcohol-induced problems than single discounting measures.