Peptide YY Causes Apathy-Like Behavior via the Dopamine D2 Receptor in Repeated Water-Immersed Mice

Apathy is observed across several neurological and psychiatric conditions; however, its pathogenesis remains unclear. We clarified the involvement of brain–gut signaling in the disruption of goal-directed behavior. Male C57BL/6J mice were exposed to water immersion (WI) stress for 3 days. Food intake and nesting behavior were measured as indexes of motivation. Repeated WI caused decrease in food intake and nesting behavior. Plasma levels of peptide YY (PYY), IL-6, and ratio of dopamine metabolites in the striatum were significantly elevated after WI. PYY and IL-6 administration significantly decreased nesting behavior. The reductions in feeding and nesting behavior were blocked by PYY receptor (Y2R) antagonist or dopamine agonist. The ameliorative effect of the Y2R antagonist was diminished by the dopamine D2 receptor (D2R) antagonist. The reduction in goal-directed behavior is associated with dysfunction of D2R signaling via increased peripheral PYY, suggesting that PYY antagonism is a novel candidate for decline of motivation in several depressive diseases. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12035-018-0931-1) contains supplementary material, which is available to authorized users.