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 D3Rmediate the metabolic side effects of APDs both centrally in the hypothalamus and peripherally in pancreas, areas critical for metabolic regulation. In Year 1 of this award, we have completed the design of a 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 D2R knockout (KO) mice. Additionally, using pancreatic islets isolated from beta cell-selective 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2018
- Accession Number
- AD1063928
Entities
People
- Zachary Freyberg
Organizations
- University of Pittsburgh