Peptide YY Causes Apathy-Like Behavior via the Dopamine D2 Receptor in Repeated Water-Immersed Mice and ninjinyoeito may improve it


Neuropsychiatric disorders often lead to various other health issues such as reduction of goal directed behaviors, apathy, incidence of co-morbidities, and eating disorders such as anorexia particularly in older patients. Apathy is a neuropsychiatric syndrome the characterized by lack of motivation, emotion imbalance, altered state of consciousness (ASOC), and intellectual impairment. The researchers were determined to figure out the primary cause of apathy like behaviors, as its pathophysiology is still unclear. The researchers studied the association of peptide YY and dopamine/ dopamine receptor with apathy like behaviors in stressed animal model.

In a recent paper published in Molecular Neurobiology journal, Tsumura Research Laboratories scientists: Dr. Chihiro Yamada, Dr. Sachiko Mogami, Dr. Hitomi Kanno and Dr. Tomohisa Hattori investigated possible risk factors involved in the pathophysiology of lack of motivation. In their studies, mice were subjected to 14 h water-immersion for three consecutive days in order to induce the stress condition. Afterward feeding and nesting patterns were monitored as the dark phase begins. Pharmacological intervention was undertaken using interleukin 6, peptide YY, neuropeptide Y receptor type 2 (Y2R) antagonist and the dopamine D2 receptor (D2R) antagonist. Levels of these test drugs were measured in plasma of subject and their effects on food intake and nesting behavior was observed.

The researchers observed significant changes in nesting behavior, food intake, body weight, and plasma content levels. The food intake of water immersed mice was reduced in the first 24 hours and then shown a gradual increase after 48 hours. High corticosteroid levels were observed in the blood profile, while the body weight and body fat of water immersed mice showed at lower values than normal mice. Nesting behavior was evaluated by nest building score from 1 to 5 point and calculating the percentages of used nest material. Those parameters showed low values in water immersed mice. . Decreased levels of leptin and increased level of ghrelin indicated the anorexic condition of water immersed mice.

In addition to the behavioral patterns examination, Tsumura researchers also examined the impact of external contribution to the target by direct administration. Exogenous administration of both interleukin 6 and peptide YY showed declined level of food intake and nesting behavior, while Y2R antagonist administration lead to positive behavioral changes in water immersed mice with blockage of further decrease in food intake. It is interesting to note that when the research team co-administration of Y2R and D2R (Dopamine receptor) antagonist to the mice, it lead to the masking of ameliorative effect of PYY receptor antagonist. The pharmacological studies conducted were strengthened by the assessment of nesting behavior.

Additionally, the researchers demonstrated in a recent study (Jpn Pharmacol Ther 2018; 46: 207-16) that ninjinyoeito (NYT), Japanese kampo medicine improved reduction of feeding and nesting behaviors of this water immersed mice (Figure 1). Interestingly, the effect of NYT on water immersed mice was completely abolished with co-administration of D2R antagonist. These results further support the hypothesis that the decline in feeding and nesting behavior in this model is likely to be involved in impaired function of D2R.

The pharmacological effect of exogenously administered interleukin 6 and peptide YY was determined for the very first time in their study and the authors concluded that these agents play a key role in reducing the food intake and nesting behavior. And they are proposing the possibility of new treatment of apathy symptoms, so called NYT administration and further research are expected in the future. The results of the study will benefit scientists in the field of neuropsychiatry and help in advancing better treatment for apathy like behaviors and their symptoms in near future.


Peptide YY Causes Apathy-Like Behavior -Medicine Innovates

About the author

Dr. Yamada is assistant manager in Department of Kampo research and development, TSUMURA & Co. She studied in biological research at Shizuoka University, and after that she acquired PhD at Hokkaido University. As an expert on research focusing on the action mechanism of eating disorders due to stress loading so far, she has explored on the relation between food-related hormones ghrelin and/or PYY(1, 2) particular, with the advent of an aging society in recent years, research on stress and sex difference of elderly people is becoming an extremely important task. In the study using older mice, the severity of eating disorder due to stress is severe in male mice compared to females(3). She was particularly interested in the assessment of apathy-like symptoms in basic research and created ideas and evidence that nest preparation could be used to evaluate one of the symptoms of apathy syndrome.

  1. Influence of Aging and Gender Differences on Feeding Behavior and Ghrelin-Related Factors during Social Isolation in Mice. PLoS One. 2015 Oct 8;10(10):e0140094.
  2. Peptide YY induces characteristic meal patterns of aged mice. Horm Behav. 2017 Nov;96:62-68.
  3. Serotonin 2C receptor contributes to gender differences in stress-induced hypophagia in aged mice. Psychoneuroendocrinology. 2015 May;55:81-93.


Yamada C, Mogami S, Kanno H, Hattori T. 2018. Peptide YY causes apathy-like behavior via the dopamine D2 receptor in repeated water-immersed mice. Molecular neurobiology. 55(9): 7555-7566.

Go To Molecular neurobiology