Abstract
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.
Highlights
Decreased motivation is often observed in psychoneurotic diseases with several depressive symptoms
We examined the involvement of dopaminergic neuron in the reduction of nesting behavior following peptide YY (PYY) administration
The effect of Y2 receptor (Y2R) antagonist was completely blocked by co-administration of dopamine type 2 receptor (D2R) antagonist
Summary
Decreased motivation is often observed in psychoneurotic diseases with several depressive symptoms. Apathy has been characterized by decreases in goal-directed behaviors and reduced motivation that frequently occurs beyond the framework of several neurological and psychiatric conditions, such as Alzheimer’s disease, major depression, and traumatic brain injury [1, 2]. The decline in goal-directed behavior and motivation for action, which are required for life support, causes decreased physical function and increased morbidity among the elderly patients and it is an important issue in the aged society [3, 4], and efforts are under way to search for effective treatments. Dopamine type 2 receptor (D2R) KO mice exhibit hypophagia [8] and impaired goaldirected motivation [9], indicating that failure of dopamine release and/or dysfunction of the D2R play important roles in the pathogenesis of apathy-like behaviors. Dopamine transporter inhibitors are reportedly effective in the treatment of apathy in a small number of patients with Alzheimer’s disease [10], the effects of dopamine replacement therapy are limited and side effects pose a problem [11]
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