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Major depression is one of the most common affective disorders caused by schizophrenia. The administration of N-methyl-D-aspartate receptor antagonists, such as ketamine, can reproduce the negative and affective symptoms of this disorder in animals. Preclinical studies have shown that 5-HT6 receptor (5-HT6R) agonists and antagonists have a considerable antipsychotic response. The aim of the present study was to evaluate the effect of an acute treatment with an agonist, E-6837, and an antagonist, SB-271046, of 5-HT6R on the immobility induced in mice by a subchronic ketamine regimen (5 days; 10 mg/kg/day, intraperitoneal). Repeated ketamine administration alone increased the immobility time in the forced-swimming test and the tail-suspension test. E-6837 at 10 and 20 mg/kg caused a significant reduction of immobility in the tail-suspension test and forced-swimming test, respectively. Interestingly, SB-271046 (10 mg/kg) also elicited an antidepressant-like effect in both tests. The current findings suggest an important role for these 5-HT6R ligands as mood modulators. However, it is necessary to explore the physiological mechanisms involved in this process in greater detail.

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Some types of schizophrenia have been associated with repetitive movements lacking specific purpose, also known as stereotyped behavior. Dopamine agonists (D2) and noncompetitive N-methyl-D-aspartate receptor antagonists (e.g. ketamine) have been administered in rodent models to induce stereotyped behavior that resembles some motor symptoms of schizophrenia. Recently, a relationship has been found between 5-HT6 receptors (5-HT6Rs) and dopaminergic activity. The present study evaluates the effect of ketamine (5 and 10 mg/kg), alone and in combination with the 5-HT6R agonist E-6837, on the climbing behavior of male mice. Ketamine was administered with an acute (1 day) and subchronic (5 day) scheme. Later, these doses and schemes were combined with an acute scheme of E-6837 (5 and 10 mg/kg). With both the acute and the subchronic schemes, ketamine increased climbing behavior at a dose of 10 mg/kg, and this effect was reversed by E-6837 (at 5 and 10 mg/kg). The present results suggest that there is an interaction between N-methyl-D-aspartate and 5-HT6 receptors in the regulation of climbing behavior. Further research is necessary to provide more evidence on this interaction.

The present data provide evidence that FS induces changes in the effect of 5-HT(1A) agents. The participation of the 5-HT and/or GABA systems in these stress-induced effects is discussed.