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

Ketamine, a drug that blocks NMDA receptors, produces rapid antidepressant-like effects in male mice, reducing immobility in a forced swimming test. At a high dose (10 mg/kg), it increased dopamine and serotonin levels in the striatum, along with dopamine metabolites DOPAC and HVA. These changes were linked to increased tyrosine hydroxylase and decreased dopamine and serotonin transporter immunoreactivities in the striatum and hippocampus. The findings suggest ketamine's antidepressant action involves enhancement of monoamine pathways, particularly by raising dopamine and serotonin availability through effects on their synthesizing enzyme and transporters.

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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. Keywords: Ketamine, Antidepressive effect, Dopaminergic neurotransmission, Serotonergic neurotransmission, Monoamine transporters