The monoaminergic pathways and inhibition of monoamine transporters interfere with the antidepressive-like behavior of ketamine

Abstract

Ketamine (KET), a NMDA receptor antagonist, has been studied for its rapid and efficacious antidepressant effect, even for the treatment-resistant depression. Although depression is a major cause of disability worldwide, the treatment can be feasible, affordable and cost-effective, decreasing the population health burden. We evaluated the antidepressive-like effects of KET and its actions on monoamine contents (DA and its metabolites, as well as 5-HT) and on tyrosine hydroxylase (TH). In addition DAT and SERT (DA and 5-HT transporters, respectively) were also assessed. Male Swiss mice were divided into Control and KET-treated groups. The animals were acutely treated with KET (2, 5 or 10 mg/kg, i.p.) and subjected to the forced swimming test, for evaluation of the antidepressive-like behavior. Imipramine and fluoxetine were used as references. The results showed that KET decreased dose-dependently the immobility time and shortly after the test, the animals were euthanized for striatal dissections and monoamine determinations. In addition, the brain (striata, hippocampi and prefrontal cortices) was immunohistochemically processed for TH, DAT and SERT. KET at its higher dose increased DA and its metabolites (DOPAC and HVA) and mainly 5-HT contents, in mice striata, effects associated with increases in TH and decreases in DAT immunoreactivities. Furthermore, reductions in SERT immunoreactivities were observed in the striatum and hippocampus. The results indicate that KET antidepressive-like effect probably involves, among other factors, monoaminergic pathways, as suggested by the increased striatal TH immunoreactivity and reduced brain DA (DAT) and 5-HT (SERT) transporters.

Rapid and long-lasting antidepressant-like effects of ketamine and their relationship with the expression of brain enzymes, BDNF, and astrocytes

“…A neural mechanism involved in the antidepressant effects of KET is the AMPA receptor stimulation, which has been shown to mediate an increase in the brain extracellular levels of serotonin, as also shown by our group ( 7 ). However, mechanisms other than NMDA receptor inhibition play a key role in the antidepressant effect of KET, suggesting that the KET antidepressant effect goes beyond the NMDA receptor inhibition and AMPA receptor activation.…”

“…This synergistic effect was probably the result of inhibitions of GSK-3 and HDAC, important targets for both drugs. Recently, we also demonstrated that the fast antidepressant effects of KET are, at least partly, due to its action on striatal monoaminergic pathways ( 7 ).…”

Antidepressant-like Effect of the Eburnamine-Type Molecule Vindeburnol in Rat and Mouse Models of Ultrasound-Induced Depression

“…Thus, it has been shown that an increase in dopamine levels accompanies the use of several antidepressants. For instance, Viana et al demonstrated that ketamine administration caused a decrease in immobility time and an increase in dopamine concentration in the striatum of mice . In some models of depression, a decrease in dopamine and norepinephrine in the striatum is observed .…”

>b<Estudos comportamentais e neurofisiológicos da exposição prolongada à cetamina como antidepressivo e o modelo de separação materna para indução de depressão pós-parto em ratos>/b<

“…Em relação ao sistema serotoninérgico, estudos mostraram que fármacos, como a fluoxetina, imipramina e cetamina aumentam a fosforilação de proteínas responsáveis pela modulação dos receptores serotoninérgicos (GRIECO et al, 2017;VIANA et al, 2018). Grieco et al (2017) ARONSTAM, 1990;ZHAO;SUN, 2008;YAMAMOTO et al, 2013).…”