Electronic Theses and Dissertations

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Browsing Electronic Theses and Dissertations by Subject "5-HT"

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    Strategies to Identify Therapeutic Opportunities in the Treatment of Addictive Disorders
    Price, Amanda Elizabeth
    Addictive disorders are a collection of maladaptive behaviors characterized by the uncontrolled use of a rewarding substance. These include substance use disorders, binge eating disorder, certain subtypes of obesity, gambling disorder, and internet gaming disorder. Each of these disorders share similar behavioral characteristics that may be motivated by common neural substrates and molecular mechanisms. This dissertation aims to elucidate some of the drivers of addictive behaviors and proposes four strategies to identify therapeutic opportunities in the treatment of addictive disorders, with a special emphasis on binge eating disorder. The current work demonstrates an association between high fat food binge intake and cue reactivity, both of which are modulated by insula activity. Further, the clinically-approved serotonin (5-HT) 5-HT2A receptor (5-HT2AR) antagonist/inverse agonist pimavanserin and 5-HT2CR agonist lorcaserin used alone or in combination demonstrate efficacy in suppressing measures of binge eating. Pharmacological studies further show that activation of the 5-HT2CR may suppress binge eating by decreasing the reinforcing and motivational properties of high fat food. Finally, a possible role for a 5-HT2AR:5-HT2CR protein interaction in the protection against addictive behaviors is proposed. This dissertation concludes by discussing possible routes of implementation of the present findings into clinical practice. The strategies discussed – neuronal modulation, behavioral-guided therapy, drug repurposing, and combined therapeutic approaches – offer great possibilities in the development of new therapeutic approaches in the treatment of addictive disorders.
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    The synthesis of 5-HT2 receptor designed multiple ligands to investigate the role of the 5-HT2AR and the 5-HT2CR in cocaine addiction
    Shashack, Matthew 1981-; Gilbertson, Scott R; Cunningham, Kathryn A; Watson, Cheryl S; Moeller, Gerard; Natarajan, Amarnath
    Previous studies indicate that the 5-HT2AR and 5-HT2CR play a role in cocaine induced behavior modification through either stimulation or inhibition respectively. Recent research has revealed that dimerization and oligomerization of GPCRs including the 5-HTRs frequently occurs. In order to target these GPCR dimers and oligomers bivalent ligands have been synthesized. Previously synthesized bivalent ligands have demonstrated increased affinity and potency when compared to administration of the monomers. The aim of this project is to synthesis homodimeric 5-HT2A R antagonists, homodimeric 5-HT2CR agonists, and heterodimeric 5-HT2A R antagonist/5-HT2CR agonist that will exhibit improved ability to control cocaine induced behavior modifications compared to the concurrent administration of a 5-HT2A R antagonist and a 5-HT2CR agonist.
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    The synthesis of 5-HT2 receptor designed multiple ligands to investigate the role of the 5-HT2AR and the 5-HT2CR in cocaine addiction
    Shashack, Matthew 1981-; Gilbertson, Scott R; Cunningham, Kathryn A; Watson, Cheryl S; Moeller, Gerard; Natarajan, Amarnath
    Previous studies indicate that the 5-HT2AR and 5-HT2CR play a role in cocaine induced behavior modification through either stimulation or inhibition respectively. Recent research has revealed that dimerization and oligomerization of GPCRs including the 5-HTRs frequently occurs. In order to target these GPCR dimers and oligomers bivalent ligands have been synthesized. Previously synthesized bivalent ligands have demonstrated increased affinity and potency when compared to administration of the monomers. The aim of this project is to synthesis homodimeric 5-HT2A R antagonists, homodimeric 5-HT2CR agonists, and heterodimeric 5-HT2A R antagonist/5-HT2CR agonist that will exhibit improved ability to control cocaine induced behavior modifications compared to the concurrent administration of a 5-HT2A R antagonist and a 5-HT2CR agonist.