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    5α-reductase isoenzymes mediate stress-exacerbated Tourette-like responses in animal models

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    Available after: 2019-05-31 (6.277Mb)
    Issue Date
    2018-05-31
    Author
    Mosher, Laura Jean
    Publisher
    University of Kansas
    Format
    270 pages
    Type
    Dissertation
    Degree Level
    Ph.D.
    Discipline
    Pharmacology & Toxicology
    Rights
    Copyright held by the author.
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    Abstract
    Tourette syndrome is a neurodevelopmental disorder characterized by purposeless, uncontrollable muscle movements known as tics. These tics are extremely sensitive to environmental factors, especially psychosocial stress. Stress has been demonstrated to increase neurosteroids in animal models, but the relationship of these neurosteroids to Tourette syndrome is unknown. The neurosteroid allopregnanolone is a key regulator of the stress cascade but has also been demonstrated to influence dopamine-mediated behaviors in animal models. Clinical results have shown that inhibiting the synthesis of allopregnanolone and other 3α, 5α steroids with the 5α-reductase inhibitor finasteride reduces tics in adult male patients with Tourette syndrome; however, the mechanism of action is largely unidentified. In this dissertation, the mechanism by which stress exacerbates Tourette syndrome symptoms and finasteride attenuates these behaviors was examined. We found that in various animal models of Tourette syndrome, stress exacerbated tic-like behaviors and deficits in prepulse inhibition (PPI), an operational measure of sensorimotor gating aimed at filtering salient information from the environment; this process is also disrupted in Tourette syndrome patients. These stress-induced tic-like behaviors and PPI deficits were ablated by finasteride treatment, which indicated a role for 3α, 5α steroids. We found that one of these steroids, allopregnanolone exacerbated tic-like behaviors and induced PPI deficits in our animal models. In addition, we determined that allopregnanolone is mediating these effects through several possible receptors; specifically we found evidence suggesting that the pregnane xenobiotic receptor and the purinergic P2X4 receptor are involved in these processes. Finally, we demonstrated that the isoenzymes 5α-reductase type 1 and type 2 exert different effects in regulating Tourette syndrome-like symptoms, and specifically that 5α-reductase type 1 may be the more beneficial and safe target for inhibition over 5α-reductase type 2.
    URI
    http://hdl.handle.net/1808/27809
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    • Dissertations [4474]
    • Pharmacy Dissertations and Theses [118]

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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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