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Saber Dissertation .pdf (2.32 MB)

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Preclinical evaluation of a potential treatment for ADHD targeting the serotonin 1B receptor subtype

Saber, Yasir Hazim
http://rave.ohiolink.edu/etdc/view?acc_num=toledo1566553528266516

Abstract Details

2019, Doctor of Philosophy, University of Toledo, Experimental Therapeutics.
Perturbations in dopamine signaling, and consequent alterations in corticostriatal function, have been implicated in attention deficit/ hyperactivity disorder (ADHD). Paradoxically, the primary treatments for ADHD are monoamine uptake inhibitors, which are psychostimulant-like drugs. However, these drugs work in only a proportion of individuals with ADHD and other concerns limit their effective use. Current non stimulant ADHD medications also have shortcomings. A crucial element of identification novel drugs treatments are valid animal models of psychiatric disorders. The experiments presented here further validated the dopamine transporter knockout (DAT KO) mouse model and then used this model to evaluate a potential new approach to the treatment of ADHD, via inhibition of the serotonin 1B receptor subtype (5HT1B). Substantial evidence has shown that DAT -/- mice exhibit ADHD-like deficits that are ameliorated by treatment with drugs that are effective ADHD therapies. However, since these mice show features that are not like ADHD, DAT +/- mice were also investigated. Additionally, sex has been an underexplored feature of this model and ADHD overall, in iv part because the presentation of ADHD symptoms is different in females. The results presented here found additional evidence that DAT -/- mice show ADHD-like phenotypes that can be reversed by effective ADHD treatments. Moreover, DAT +/- mice also exhibited ADHD-like phenotypes, although less severe than DAT -/- mice, and these deficits could be reduced by effective ADHD treatments as well. Both the deficits and responses to effective ADHD treatments were sex dependent – both males and females showed similar deficits, but males were more effected in some symptom realms and females in others. Finally, the 5HT1B receptor antagonist SB 224289 reduced many of the deficits in both DAT –/- and DAT +/- mice, and importantly were shown to reduce impulsivity in the 5-Choice Continuous Performance Test in DAT +/- mice. In summary the data in this thesis provide additional evidence for the validity of the DAT KO model, and in particular the DAT +/- model, as well as evidence supporting the potential of 5HT1B antagonism as a potential new, non-stimulant approach to the treatment of ADHD.
Scott Hall (Advisor)
Frederick Williams (Committee Member)
Yousef Sari (Committee Member)
Zahoor Shah (Committee Member)
317 p.
Pharmacology; Physiology
ADHD, Dopamine transporter ko mice, serotonin 1b antagonist, 5-choice continuous performance test, cliff avoidance reaction, locomotor activity, prepulse inhibition, social isolation, atomoxetine, amphetamine

Recommended Citations

Citations

  • Saber, Y. H. (2019). Preclinical evaluation of a potential treatment for ADHD targeting the serotonin 1B receptor subtype [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1566553528266516

    APA Style (7th edition)

  • Saber, Yasir. Preclinical evaluation of a potential treatment for ADHD targeting the serotonin 1B receptor subtype . 2019. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=toledo1566553528266516.

    MLA Style (8th edition)

  • Saber, Yasir. "Preclinical evaluation of a potential treatment for ADHD targeting the serotonin 1B receptor subtype ." Doctoral dissertation, University of Toledo, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1566553528266516

    Chicago Manual of Style (17th edition)

toledo1566553528266516
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This open access ETD is published by University of Toledo and OhioLINK.