Feeding behavioral pharmacogenetics of a murine model of the OPRM1 A118G polymorphism
Description
TitleFeeding behavioral pharmacogenetics of a murine model of the OPRM1 A118G polymorphism
Date Created2019
Other Date2019-10 (degree)
Extent1 online resource (xv, 138 pages) : illustrations
DescriptionBinge eating disorder (BED) is the most prevalent eating disorder, and is characterized by a perceived “loss of control” over ones food intake, resulting in the consumption of large amounts of food in short periods of time. There is currently one FDA-approved drug for the treatment of BED, lisdexamfetamine dimesylate. A common single nucleotide polymorphism (SNP) of the mu-opioid receptor gene (OPRM1 A118G) results in an amino acid substitution (N40D) in the extracellular domain that is posited to alter receptor stability and ligand binding. The OPRM1 A118G SNP has been associated with alterations in nociception and analgesia, as well as altered susceptibility to substance abuse. GG allele status has also been associated with BED in an obese population, as well as increased preference and intake of highly-palatable foods. In this dissertation, an established rodent model of binge-like feeding was utilized to investigate the role of the homologous SNP in mice (OPRM1 A112G; N38D) in binge propensity, pharmacological efficacy, and taste and meal phenotyping in male and female mice. The 6-wk, intermittent 24-hr caloric restriction and/or 30-min subsequent binge access feeding schedules (Restrict, R; Binge, B; Restrict-Binge, RB; Naïve, N) revealed no differences in binge intakes between AA and GG genotypes in male or female mice. Following the 6-wk protocol, female mice underwent acute or chronic dosing schedules: within-group, 1x/wk dosing of vehicle (Veh; water), lisdexamfetamine dimesylate (LDX; 0.15, 0.5, 1.5 mg/kg), and sibutramine hydrochloride (Sib; 0.3, 1.0, 3.0 mg/kg); or between-group, 2-wk daily dosing of either Veh, Sib (3.0 mg/kg), or LDX (1.5 mg/kg), respectively. There was no effect of AA or GG genotype on pharmacotherapeutic efficacy in reducing binge-like feeding. Two-bottle lipid preference tests in male mice previously exposed to the 6-wk feeding schedules revealed increased preference for Intralipid (IL) in R and RB groups compared to N, for 5% IL only, and N GG had lower preference than N AA mice. Genotype differences in brief-access taste responsivity in male and female mice were observed only in sweet, nutritive carbohydrate taste stimuli. There was no effect of genotype on meal microstructure in male mice, but female GG mice had larger average meal sizes and greater total caloric meal intakes. Although there may be some elements of taste and meal patterns mediated by OPRM1 A112G SNP status, our data does not support a role for this common SNP in the predisposition to binge-like feeding nor the efficacy of pharmacotherapy. While the concept of “personalized medicine” remains intriguing, the current studies do not suggest a role for the involvement of the OPRM1 A118G SNP in binge eating disorder.
NotePh.D.
NoteIncludes bibliographical references
Genretheses, ETD doctoral
LanguageEnglish
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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