Involvement of Brain 5-HT7 Receptors in the Formation of Stress Adaptation in Mice

Abstract

Background/Objectives: Impairment of the ability to adapt to stress in animals may contribute to some stressrelated psychiatric disorders, such as anxiety and depression. A growing body of evidence has suggested that the brain's serotonin (5-HT) nervous system may play an important role in the etiology, expression and treatment of anxiety and depression. The aim of the present study was to examine whether brain 5-HT 7 receptors are involved in the formation of stress adaptation. Methods:Male ICR mice were either exposed to repeated restraint stress for 60 or 240 min/day (stressed group) or left in their home cage (non-stressed group) for 1 or 14 days. The emotionality of mice was estimated by the hole-board test. The levels of 5-HT 7 receptor expression and extracellular signal-regulated kinase 1/2 (ERK) phosphorylation were assessed by western blot analysis. Results:A single exposure to restraint stress for 60 min induced a decrease in head-dipping behavior in the hole-board test. This emotional stress response was not observed in mice that had been exposed to repeated restraint stress for 60 min/day for 14 days, which confirmed the development of stress adaptation. In contrast, mice that were exposed to restraint stress for 240 min/day for 14 days did not develop this stress adaptation, and still showed a decrease in head-dipping behavior. Increases in 5-HT 7 receptor protein and ERK phosphorylation were observed in the frontal cortex and hippocampus of stress-adaptive, but not stress-maladaptive, mice. The decreased emotionality observed in stress-maladaptive mice was significantly recovered by chronic treatment with LP-12, a selective 5-HT 7 receptor agonist, immediately after daily exposure to stress. Conclusion:The present findings suggest that the brain 5-HT 7 receptor-ERK system may play an important role in the formation of stress adaptation. Furthermore, stimulation of 5-HT 7 receptors may have a beneficial effect on stress adaptation and alleviate the emotional abnormality observed under conditions of excessive stress.

Pharmacology and Therapeutic Potential of the 5-HT7 Receptor

“…Most recently, Takeda et al identified a relationship between 5-HT 7 activation and stress adaptation. In that study, a single exposure to 60 min of restraint stress caused a reduction in the head-dipping response in the hole-board test.…”