The 5-HT6R agonist E-6837 and the antagonist SB-271046 reverse the psychotic-like behaviors induced by ketamine

Ketamine, an anesthetic that blocks NMDA receptors, can produce symptoms resembling schizophrenia. In mice, five daily injections of ketamine (10 mg/kg) caused memory deficits, anxiety, obsessive-compulsive behaviors, and stereotyped movements. Two experimental drugs targeting the 5-HT6 receptor—an agonist (E-6837) and an antagonist (SB-271046)—each reversed the memory impairment and reduced anxiety when given alone. SB-271046 also decreased climbing behavior. Neither drug affected the light–dark test. Unexpectedly, when either drug was combined with ketamine, anxiety worsened. Both types of 5-HT6 drugs appear to modulate psychotic-like symptoms caused by blocking NMDA receptors.

Study at a glance

Abstract

Schizophrenia is a serious mental disorder that affects 1% of the world’s population. Although various therapeutic tools have been developed since the appearance of the first generation of antipsychotics, the effect of these agents does not manage to attenuate a significant part of psychotic symptoms. Ketamine is an anesthetic agent able to produce psychotic-like symptoms through the antagonism of the glutamatergic N-methyl-d-aspartic acid (NMDA) receptors (NMDARs). This drug has been widely used to study new pharmacological tools with potential antipsychotic properties. On the contrary, it is known that the 5-HT6 receptor agonist and antagonist drugs induce procognitive, anxiolytic and antidepressant effects in different preclinical models. Therefore, the aim of this study was to evaluate the behavioral actions of the 5-HT6 receptors’ agonist E-6837 and the antagonist SB-271046, in ICR-CD1 mice previously treated with a subchronic ketamine scheme (10 mg/kg i.p. daily for 5 days). Results showed that repeated administration of ketamine induced recognition memory deficit, anxiogenic effects, obsessive-compulsive behaviors and stereotyped movements. The acute administration of both 5-HT6 agents reversed the memory deficit and induced a decrease in anxiety, whereas SB-271046 administration produced a decrease in climbing behavior. The injection of either of these 5-HT6 drugs had no effect in the light–dark test. Surprisingly, when these drugs were injected together with ketamine, anxiogenic actions were produced. Current findings suggest that both agonist and antagonist 5-HT6 drugs play an important role in modulating psychotic-like symptoms induced by the subchronic blockade of NMDAR.