Ketamine improved depressive-like behaviors via hippocampal glucocorticoid receptor in chronic stress induced- susceptible mice

Highlights

• Susceptible mice showed depressive-like behaviors upon chronic social defeat stress.

• Plasma corticosterone concentration might predict susceptibility to chronic stress.

• Abnormal glucocorticoid receptor expression was associated with susceptibility.

• Ketamine exerted antidepressant effect via normalizing HPA axis response.

Abstract

Chronic stress is an important factor for depression. Most individuals recover from stress, while some develop into depression. The pathogenesis of resilience or susceptibility remains unclear. Stress activates the hypothalamic-pituitary-adrenal (HPA) axis and releases stress hormones to regulate individual response to stress. Hence, we assessed the effects of chronic social defeat stress (CSDS) on susceptible behaviors, plasma corticosterone (CORT) concentration, glucocorticoid receptor (GR) expressions in hippocampus and medial prefrontal cortex (mPFC). Mice that plasma CORT concentration is increased 2 h after single social defeat stress developed into susceptible mice after 10 d social defeat stress. The plasma CORT concentration was still higher than that of resilient mice 48 h after the last defeat stress. Mice administered CORT via drinking water showed susceptibility. Mifepristone, a GR antagonist improved susceptibility to chronic stress. Single dose ketamine treatment improved depressive-like behaviors, decreased plasma CORT concentration, rescued GR expression and nuclear translocation in the hippocampus of susceptible mice. These results suggested that abnormal CORT concentration after stress may predict susceptibility to depression in clinic. Ketamine may exert the antidepressant effect via normalizing HPA axis response and have significance in the clinic.

Introduction

Major depressive disorder (MDD) is a common neuropsychiatric disorder that affects approximately 300 million people worldwide [1]. Depression is mainly manifested as depressed mood, retardation of thought, loss of interest and enjoyment, and decline of cognitive function. It could even lead to suicide in some patients, bringing a heavy burden to patients, families and society. Stress event is an important factor for depression [2]. Most individuals recover to normal state after stress, while some develop into depression. The pathogenesis of susceptibility or resilience remains unclear [[3], [4], [5], [6]].

The hypothalamic-pituitary-adrenal (HPA) axis is activated upon stress. Stress hormones such as glucocorticoid (cortisol in humans, corticosterone (CORT) in rodents) are secreted by the adrenal cortex. Glucocorticoid imbalance hypothesis has been paid more attention [7]. Glucocorticoid combined with CORT receptors (GRs) in hippocampus, prefrontal cortex and other brain regions to play roles in adjusting individual to cope with stress and form a negative feedback mechanism [2]. Cortisol concentration in the serum or saliva is increased in depressive patients [[8], [9], [10]]. Postmortem analyses of depressed suicide patients have revealed that GR mRNA level is decreased in the hippocampus and the cortex [11]. Rodent experiments have revealed that GR deficits in the prefrontal cortex of mice lead to depressive-like behaviors [12]. GR antagonist enhanced the antidepressant effect of fluoxetine [13], and the GR antagonist RU-43044 alone can also improve depressive-like behaviors in mice [14]. The antidepressant sertraline increases hippocampal neurotransmission via a GR-dependent pathway [15]. Patients with excessive glucocorticoid are more likely to experience depression recurrence. These findings suggest that CORT and their receptors are involved in the pathological process and treatment of depression [16]. But it’s still unknown whether the CORT and GRs are relevant to susceptibility or resilience.

The traditional antidepressant agents such as tricyclic antidepressants, serotonin reuptake inhibitors and norepinephrine reuptake inhibitors, are aimed at inhibiting reuptake of neurotransmitter and increasing the concentration of synaptic monoamine neurotransmitters to produce antidepressant effects. These antidepressant drugs work slowly and usually it takes 4–6 weeks to achieve the effect. Furthermore, they are ineffective in about one-third of patients. Patients are still characterized by a high risk of suicide at the beginning of the treatment period [17]. The mechanism by which patients have low response to antidepressant remains unclear. Some studies suggest that hyperactivity of the HPA-axis can predict worse treatment outcome [18]. High HPA-axis activity is related with risk of relapse of depression [19]. These evidences suggest that the stress system plays an important role in the development of depression.

Ketamine has recently been found to exert rapid and sustained antidepressant effect. Single dose ketamine can have an efficacy of up to 1 week [20]. Furthermore, ketamine is an effective drug against refractory depression [21,22]. The antidepressant mechanism of ketamine is still unclear. Whether CORT and GRs are involved in ketamine's antidepressant effects remain unclear, representing a key aspect of our study.

Chronic social defeat stress (CSDS) is a classic depression model in rodents. Social defeat-stressed mice can divide to susceptible and resilient populations by the social interaction (SI) test, as susceptible mice show depressive-like behaviors, while resilient mice do not. Insight into the biology of variations in susceptibility can be gained by understanding individual differences in response to stress.

In the present study, we first constructed a CSDS model to investigate the relationship between stress susceptibility and plasma CORT concentration in mice. We found that plasma CORT concentration was increased in susceptible mice. Mice administered CORT via drinking water showed susceptibility. GR antagonists improved chronic stress susceptibility in mice. Furthermore, we found that ketamine treatment exerted antidepressant effects in stress-susceptible mice via adjusting GR expression in hippocampal and plasma CORT concentration. This will provide a clinical significance that plasma corticosterone concentration might predict susceptibility to chronic stress and the clinical prospect of ketamine in the treatment of depression.