Browsing by Subject "Rodent model"

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    Bidirectional enantioselective effects of the GABAB receptor agonist baclofen in two mouse models of excessive ethanol consumption
    (Elsevier, 2015-02) Kasten, Chelsea R.; Blasingame, Shelby N.; Boehm, Stephen L.; Department of Psychology, School of Science
    The GABAB receptor agonist baclofen has been studied extensively in preclinical models of alcohol-use disorders, yet results on its efficacy have been uncertain. Racemic baclofen, which is used clinically, can be broken down into separate enantiomers of the drug. Baclofen has been shown to produce enantioselective effects in behavioral assays, including those modeling reflexive and sexual behavior. The current studies sought to characterize the enantioselective effects of baclofen in two separate models of ethanol consumption. The first was a Drinking-in-the-Dark procedure that provides "binge-like" ethanol access to mice by restricting access to a 2-h period, 3 h into the dark cycle. The second was a two-bottle choice procedure that utilized selectively bred High Alcohol Preferring 1 (HAP1) mice to model chronic ethanol access. HAP1 mice are selectively bred to consume pharmacologically relevant amounts of ethanol in a 24-h two-bottle choice paradigm. The results showed that baclofen yields enantioselective effects on ethanol intake in both models, and that these effects are bidirectional. Total ethanol intake was decreased by R(+)-baclofen, while total intake was increased by S(-)-baclofen in the binge-like and chronic drinking models. Whereas overall binge-like saccharin intake was significantly reduced by R(+)-baclofen, chronic intake was not significantly altered. S(-)-baclofen did not significantly alter saccharin intake. Neither enantiomer significantly affected locomotion during binge-like reinforcer consumption. Collectively, these results demonstrate that baclofen produces enantioselective effects on ethanol consumption. More importantly, the modulation of consumption is bidirectional. The opposing enantioselective effects may explain some of the variance seen in published baclofen literature.
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    Targeting Early Vascular Dysfunction Following Spinal Cord Injury
    (2019-10) Chen, Chen; Cummins, Theodore R.; Jin, Xiaoming; Jones, Kathryn J.; Yoder, Karmen; Xu, Xiao-ming
    The vascular network highly coordinates with the central nervous system (CNS) on exchanging oxygen, nutrients and information transfer. The resemblance of the two systems at anatomical, cellular, and molecular levels also demonstrates their interdependence. The spinal cord is an integrated part of the CNS. Traumatic spinal cord injury (SCI) causes rapid systemic vascular responses and local neural tissue damage at the initial phase. The early disruption of the spinal vasculature breaks the supply-and-demand balance and facilitates the deterioration of the spinal cord tissue and functional deficits. Therefore, it is important to dissect the mechanism underlying vascular injury-mediated histological and functional consequences in order to develop potential therapeutic strategies. To visualize dynamic vascular changes after an acute SCI, a novel duo-color in vivo imaging technique was successfully developed in adult rats at the cervical level. This technique overcomes previous technical hurdles allowing real-time observation of vascular changes in live animals. Correlated with histological measures, in vivo vascular outcomes revealed a temporospatial relationship with neuronal and axonal loss, myelin disruption, inflammation, and glial responses. For the first time, we defined a “transitional zone” where significant blood vessel dilation and vascular leakage were observed simultaneously with vascular changes occurred at the injury epicenter acutely after SCI. These vascular changes at the transitional zone happened before any other cellular damage after SCI, suggesting a time window to prevent further neuronal damage in this region. Targeting the observed vascular leakage can work as a proof of concept that early vascular dysfunction contributes to the secondary neural tissue damage. Indeed, intravenous delivery of ferulic acid conjugated with glycol chitosan (FA-GC) to the injured sites immediate after SCI resulted in reduced vascular leakage, ventral horn neuronal loss, and partial recovery of forelimb function following a clinically-relevant contusive SCI at the 7th cervical spinal cord level. In conclusion, this work elucidated a novel role and mechanism of early vascular damage in the “transitional zone” prior to the secondary damage of neural tissue in this region and provided a novel treatment strategy for early neuroprotection and functional recovery.