Central and Peripheral Mechanisms of Antipsychotic Medication-Induced Metabolic Dysregulation
Abstract
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 and/or 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2019
- Accession Number
- AD1088406
Entities
People
- Zachary Freyberg
Organizations
- University of Pittsburgh