Central and Peripheral Mechanisms of Antipsychotic Medication-Induced Metabolic Dysregulation
Technical Report,30 Sep 2018,29 Sep 2019
University of Pittsburgh Pittsburgh United States
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Antipsychotic drugs APDs are widely used psychotropic medications , though they have significant metabolic side effects. While the mechanisms for these metabolic disturbances are poorly understood, the single known unifying property of all APDs is their blockade of the dopamine D2 D2R and D3 D3R receptors. We therefore hypothesize that D2R andor D3R mediate the metabolic side effects of APDs both centrally in the hypothalamus and peripherally in pancreas , areas critical for metabolic regulation. We have completed construction of novel inducible transgenic hypothalamic- and pancreatic beta cell -specific D2R knockout KO mice and are finalizing construction of hypothalamic and pancreatic beta cell-selective D3R KO mice. Additionally, using pancreatic islets isolated from beta cell-specific D2R KO mice and complete D3R KO mice, we found diminished inhibition of stimulated insulin secretion in both strains relative to littermate controls, suggesting a role for both receptors in mediating insulin secretion. In parallel, we have developed novel assays for measurement of pancreatic alpha cell glucagon and shown that APDs act directly on alpha cells to significantly disturb glucagon release.
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