The 5-HT6R agonist E-6837 and the antagonist SB-271046 reverse the psychotic-like behaviors induced by ketamine
José Eduardo Suárez-Santiago, Gabriel Roldán Roldán, Ofir Picazo Picazo
Behavioural Pharmacology June 1, 2022 DOI: 10.1097/fbp.0000000000000669 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | ICR-CD1 mice |
| Interventions | E-6837 SB-271046 Ketamine |
| Dose | 10 mg/kg i.p. daily for 5 days |
| Duration | 5-day subchronic ketamine treatment |
| Topics | Esketamine Ketamine |
| Key points | Both a 5-HT6 receptor agonist (E-6837) and antagonist (SB-271046) reversed memory deficits and reduced anxiety caused by subchronic ketamine in mice, but combining either drug with ketamine produced anxiogenic effects. |
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.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cites 4
- Long-lasting effects of repeated ketamine administration in adult and adolescent rats. Behavioural Brain Research September 2, 2019
- Reduced auditory evoked gamma-band response and schizophrenia-like clinical symptoms under subanesthetic ketamine Neuropsychopharmacology February 6, 2019
- Agonist E-6837 and antagonist SB-271046 of 5-HT6 receptors both reverse the depressive-like effect induced in mice by subchronic ketamine administration Behavioural Pharmacology October 1, 2017
- GLYX-13 (rapastinel) ameliorates subchronic phencyclidine- and ketamine-induced declarative memory deficits in mice. Behavioural Brain Research February 15, 2016