Chronic Clomipramine Treatment Reverses Core Symptom of Depression in Subordinate Tree Shrews

Jing Wang,Lin Xu,Liping Wang,Qixin Zhou,Yuexiong Yang,Anping Chai,Longbao Lv,Yong-Gang Yao

doi:10.1371/journal.pone.0080980

Abstract

Chronic stress is the major cause of clinical depression. The behavioral signs of depression, including anhedonia, learning and memory deficits, and sleep disruption, result from the damaging effects of stress hormones on specific neural pathways. The Chinese tree shrew (Tupaia belangeri chinensis) is an aggressive non-human primate with a hierarchical social structure that has become a well-established model of the behavioral, endocrine, and neurobiological changes associated with stress-induced depression. The tricyclic antidepressant clomipramine treats many of the core symptoms of depression in humans. To further test the validity of the tree shrew model of depression, we examined the effects of clomipramine on depression-like behaviors and physiological stress responses induced by social defeat in subordinate tree shrews. Social defeat led to weight loss, anhedonia (as measured by sucrose preference), unstable fluctuations in locomotor activity, sustained urinary cortisol elevation, irregular cortisol rhythms, and deficient hippocampal long-term potentiation (LTP). Clomipramine ameliorated anhedonia and irregular locomotor activity, and partially rescued the irregular cortisol rhythm. In contrast, weight loss increased, cortisol levels were even higher, and in vitro LTP was still impaired in the clomipramine treatment group. These results demonstrate the unique advantage of the tree shrew social defeat model of depression.

Highlights

Major depressive disorder is characterized by low mood, loss of interest or pleasure in normally enjoyable activities, feelings of guilt, and chronic lack of energy
Clomipramine partially reversed anhedonia and fatigue associated with chronic social defeat
To examine whether clomipramine can ameliorate depressionlike behaviors in tree shrews, we compared sucrose preference and locomotion (Fig. 3)

Summary

Introduction

Major depressive disorder is characterized by low mood, loss of interest or pleasure in normally enjoyable activities, feelings of guilt, and chronic lack of energy. It is a neuropsychiatric syndrome characterized by impaired structural and synaptic plasticity as well as neuronal damage [1]. The hippocampus provides negative feedback to the HPA axis and is critical for certain forms of learning and memory [5]. Activity-dependent synaptic plasticity is believed to be a neurocellular mechanism underlying some forms of learning and memory, and hippocampal synapses demonstrate several forms of synaptic plasticity [8,9]. Stress impairs longterm potentiation (LTP) and enhances long-term depression (LTD) in the hippocampus in vitro and in vivo [10,11,12]

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Conclusion