Short ReportThe 5-HT6R agonist E-6837 and the antagonist SB-271046 reverse the psychotic-like behaviors induced by ketamineSuárez-Santiago, José Eduardoa,b; Roldán Roldán, Gabriela; Picazo Picazo, Ofirb Author Information aDepartamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México bLaboratorio de Farmacología Conductual, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México, México Received 6 September 2021 Accepted as revised 20 December 2021 Correspondence to José Eduardo Suárez Santiago, PhD, Escuela Superior de Medicina, Calle Salvador Díaz Mirón S/N, Santo Tomás, 11340 Ciudad de México, Ciudad de México, México, E-mail: [email protected] Behavioural Pharmacology: June 2022 - Volume 33 - Issue 4 - p 249-254 doi: 10.1097/FBP.0000000000000669 Buy Metrics 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. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.