Central and Peripheral Mechanisms of Antipsychotic Medication-Induced Metabolic Dysregulation
Technical Report,30 Sep 2018,29 Sep 2019
Albert Einstein College of Medicine New York 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 andorD3R mediate the metabolic side effects of APDs both centrally in the hypothalamus and peripherally in pancreas, areas critical for metabolic regulation. In Year 3 of this award, we have completed the design of a novel inducible D3R-flox mouse in order to selectively knock out expression of D3R in the hypothalamus and pancreatic beta cells. The resulting transgenic mice are being tested to confirm the successful production of the strain. In parallel, we have completed construction of novel inducible transgenic hypothalamic- and pancreatic beta cell-specific D3R knockout KO mice. Additionally, using pancreatic islets isolated from beta cell-selective D2R KO mice and whole body D3R KO mice we found diminished inhibition of stimulated insulin secretion in the central nervous system and the periphery relative to littermate controls, suggesting a role for both receptors in mediating insulin secretion. We did not identify major metabolic deficits in central neuronal Nkx 2.1 D3R knockouts relative to their respective controls.
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