br Introduction Depression is a prevalent and disabling psyc

Introduction Depression is a prevalent and disabling psychiatric illness that affects millions of individuals worldwide, resulting in enormous personal suffering and public health costs [1]. Traditional antidepressants such as monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors (SSRIs) usually take weeks to months to produce a therapeutic response, and more than 30% of patients with depression exhibit refractory or intolerant responses to current available antidepressant medications [2]. In contrast, recent clinical studies have demonstrated that the N-methyl-d-aspartate (NMDA) antagonist ketamine induces a rapid (withinh) antidepressant response [3], [4], and is effective in patients with major depressive disorder who are treatment-resistant to traditional antidepressants [5]. However, the molecular mechanisms underlying this process remain unclear. Multiple lines of evidence have supported a critical role for the glutamatergic system in the pathophysiology of depression, and it is believed to be a key target in mood regulation [6], [7]. Glutamate is a critical excitatory neurotransmitter in the mammalian brain, and its reuptake is essential for normal synaptic transmission. High levels of extracellular glutamate can mediate excitotoxicity and is implicated in the pathogenesis of many brain diseases [8]. However, the clearance of released glutamate is not assumed by its synaptic degradation. Excitatory amino 86 5 transporters (EAATs), also named glutamate transporters, transport glutamate from the extracellular to the intracellular spaces, thereby efficiently controlling the extracellular concentration of glutamate [9]. Currently, five distinct EAATs (EAAT1-5) that transport glutamate have been cloned. EAAT1 and EAAT2 are predominantly localized on astrocytes and abundant in the hippocampus and cerebral cortex. In contrast, EAAT3 is a neuronal transporter, which is expressed in the pre-and postsynaptic regions of neurons, while EAAT4 and EAAT5 appear mainly restricted to expression on the cerebellum and the retina, respectively [10]. Our previous study found that EAAT2 expression was markedly downregulated in the hippocampus of depressive-like rats [11]. However, whether the antidepressant effect of ketamine is related to regulating glutamate reuptake functions requires further study.
Materials and methods
Results
Discussion The present study demonstrated that glutamate reuptake dysfunction is involved in the pathogenesis of depression. The expression of EAATs, especially EAAT2 and EAAT3, was obviously downregulated, and extracellular glutamate levels were significantly increased in the hippocampi of depressive-like rats. Sub-anesthetic doses of ketamine (10, 25, and 50mg/kg) upregulated the expression of EAAT2 and EAAT3, decreased the concentration of extracellular glutamate in the hippocampus, and thus effectively alleviated the depressive-like behavior of rats. Additionally, we found that the antidepressant effect of ketamine was associated with its doses. For example, 25mg/kg of ketamine showed a better antidepressant effect, and the antidepressant effect of ketamine gradually weakened with the increase in doses (50mg/kg). CUMS is a common method to establish an animal model of depression [12]. Anhedonia, namely the ability to experience pleasure decline, is a core symptom of depression, which can be evaluated in rodents by sucrose preference percentage (SPP) and exploratory activities [13]. In this study, the SPP and exploratory activities of CUMS-treated rats significantly decreased compared to those in the control group, which indicates that the model of depression was successfully established. In addition, our results showed that repeated administration of sub-anesthetic doses of ketamine (10, 25, and 50mg/kg) significantly increased the SPP and exploratory activities of rats, and improved their depressive-like behavior. Our results are consistent with those of previous studies reporting that a single dose of ketamine possesses rapidly acting antidepressant properties [17].