A pharmacological and brain imaging study of human vasopressin AVP1BR receptor functional polymorphisms

In humans, vasopressin AVP1BR receptor (hV_1B) plays key roles in hypothalamic-pituitary-adrenal (HPA) axis regulation and social behavior. Three hV_1B polymorphisms, rs35369693 (K65N), rs28632197 (R364H) and rs33990840 (G191R), have been related to psychiatric disorders with altered HPA axis function and social behavior. The aim of this study was to explore hV_1B pharmacological properties as a function of the polymorphism in transfected cells and the brain functioning in an emotional task in volunteers harboring different AVP1BR polymorphisms. Transfection rate, fluorescent imaging and inositol phosphate (IPs) accumulation were evaluated in HEK293 cells that expressed different hV_1B variants: K65/G191/R364 (wild type), G191R, K65N and/or R364H. Brain functional activity was investigated in 35 healthy men with different hV_1B variants during an fMRI implicit emotional recognition paradigm. IPs accumulation after arginine vasopressin stimulation was much reduced in cells expressing hV_1B K65N and/or R364H, and increased in cells expressing G191R. Basal IPs accumulation, transfection rate, and fluorescent binding to plasma membrane were similar for all polymorphisms. During the anger vs. neutral face visualization task, activation of motor areas, visual areas, frontal sub-gyral area, hippocampus, and putamen was higher in homozygotes for the K65/R364 haplotype than in heterozygotes. Analyses did not include participants with the G191 polymorphism because of its low frequency. Different hV_1B polymorphisms could be candidates as biomarkers of psychiatric disorders. Moreover, hV_1B may be a pharmacological target if these polymorphisms are considered.