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  • In vitro studies have shown that some antidepressant drugs

    2022-08-05

    In vitro studies have shown that some antidepressant drugs bind to NMDA receptors and inhibit the binding of NMDA receptor ligands [18]. Similarly, several research teams have reported that tricyclic antidepressants can modulate the release and/or uptake of glutamate [19]. In this study, we found that EAAT Indirubin mg was obviously downregulated, and glutamate uptake function decreased in the hippocampus of depressive-like rats. NMDA receptor antagonist ketamine reversed the depressive disorder-induced downregulation of EAAT expression and effectively alleviated the depressive-like behavior of rats. Our results further strengthened the opinion that glutamatergic system abnormality is an important pathologic basis of depressive disorder. In addition, previous studies have demonstrated that glutamate receptor activity can influence the expression of EAATs, and ionotropic glutamate receptor agonists decreased EAAT1 mRNA and protein levels [20], [21]. Therefore, our results cannot rule out the possibility that ketamine’s effects on EAAT expression are linked to its antagonistic effect on NMDA receptors. This requires further study. Concerns about the psychomimetic effects of ketamine have limited its large-scale clinical application, especially for patients with mood disorders. However, preliminary clinical studies have shown the safety of sub-anesthetic doses of ketamine as an antidepressant [17]. Ketamine at 50mg/kg dose has been considered as a sub-anesthetic or intermediate dose in humans and is most likely at the upper limit of the sub-anesthetic dose in rats[22]. In the present study, 25mg/kg of ketamine showed a better antidepressant effect. When the dose increased to 50mg/kg, the antidepressant effect of ketamine weakened. The reasons for this phenomenon may be attributed to the EAAT3 expression changes in the hippocampus. That is, the higher the expression of EAAT3 (25mg/kg of ketamine), the better is the antidepressant effect. Although glial transporters (EAAT1 and EAAT2) are believed to be responsible for most glutamate uptake Indirubin mg [23], the importance of neuronal transporters (EAAT3) has recently been recognized. In certain brain regions such as the cerebral cortex and hippocampus, a large number of synapses are not surrounded by glial processes, suggesting that neuronal transporters also play an important role in glutamate uptake and synaptic function in these regions [24]. It has been well established that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking and redistribution is crucial for synaptic plasticity [25], and the antidepressant effects of ketamine appear to be primarily mediated through regulating AMPA receptors [26]. Recent research has found that the EAAT3 plays a key role in AMPAR distribution and turnover. Inhibition of EAAT3 leads to rapid reduction in synaptic AMPAR accumulation and total receptor amount [21]. Combining this evidence and our results, we believe that neuronal transporters, such as glial transporters, play an important role in the antidepressant effect of ketamine. Additionally, ketamine 50mg/kg produced a smaller antidepressant effect than ketamine 10 or 25mg/kg. A reasonable explanation for this is that higher doses of ketamine may excessively suppress synaptic N-methyl-d-aspartate receptor (NMDA) receptor activities, which interfere with normal synaptic transmission. It has been reported that NMDA receptors have dual characteristics: physiological or synaptic NMDA receptor activation induces neuroprotection, while pathological or extrasynaptic NMDA receptor activation mediates neurotoxicity [27]. Therefore, too much NMDA receptor activity is harmful to neurons, but too little is harmful as well. One limitation of this study is that our data cannot effectively reflect the dose-effect relationship of ketamine because the observation was restricted to three dosage groups.
    Conflict of interest