Effect of 5-HT6 Receptor Ligands Combined with Haloperidol or Risperidone on Antidepressant-/Anxiolytic-Like Behavior and BDNF Regulation in Hippocampus and Prefrontal Cortex of Rats

Abstract

Background The presence of depressive and anxiety symptoms in patients with schizophrenia may have an important impact on treatment and compliance. Hence, interventions addressing such comorbidity in schizophrenia should be explored. One target may be a serotonergic 5-HT 6 receptor (5-HT 6 R) since its ligands displayed antidepressant- and anxiolytic-like activities in preclinical experiments. Methods Acute and chronic (21 days) administration of haloperidol or risperidone in combination with a selective 5-HT 6 R agonist (WAY-181187) or antagonist (SB-742457) to rats was performed for detecting antidepressant- and anxiolytic-like behaviors. In addition, the level of brain-derived neurotrophic factor (BDNF) protein and its gene expression in hippocampus and prefrontal cortex were determined. Results Both single and chronic administration of WAY-181187 with haloperidol produced antidepressant- and anxiolytic-like activities. SB-742457 did not provide full benefits in terms of improvement of haloperidol-induced adverse mood effects. However, the administration of SB-742457 with risperidone triggered its anxiolytic-like activity. Both 5-HT 6 R ligands evoked no changes in haloperidol-induced effects on BDNF level. WAY-181187 induced repression of the BDNF gene while SB-742457 increased its expression in both structures. 5-HT 6 R ligands, when combined with risperidone, did not change BDNF protein level and increased gene expression in the hippocampus, while they elevated BDNF level and potentiated gene expression in the prefrontal cortex. Conclusion The combined administration of WAY-181187 and haloperidol provided the greatest benefits, which were manifested by antidepressant-like effects and suppression of the anxiogenic-like properties. The combined administration of risperidone with both agonist and antagonist resulted only in an anxiolytic-like effect. It seems that the anxiolytic-like effects induced by haloperidol or risperidone with the addition of 5-HT 6 R ligands are task-specific. The data on BDNF protein and gene expression did not fully correspond with the behavioral outcomes, and thus it appears that other factors/mechanisms are involved in the observed antidepressant- and/or anxiolytic-like effects.

Selective 5-HT6 Receptor Ligands (Agonist and Antagonist) Show Different Effects on Antipsychotic Drug-Induced Metabolic Dysfunctions in Rats

“…Haloperidol (TargetMol, Boston, MA, USA), risperidone (TargetMol), olanzapine (TargetMol), WAY-181187 (oxalate; Tocris Bioscience, Bristol, UK), and SB-742457 (TargetMol) were used in the experiment. Doses of APDs (haloperidol 0.5 mg/kg, risperidone 0.5 mg/kg, and olanzapine 5 mg/kg) and 5-HT 6 ligands (WAY-181187 3 mg/kg and SB-742457 3 mg/kg) were selected for the experiments, based on literature review and our previous studies which presented their separate and combined behavioral effects [ 54 ]. The compounds were suspended in a 1% solution of Tween 80 (Sigma Aldrich, St. Louis, MO, USA) immediately before administration and injected intraperitoneally (ip) in a volume of 2 mL/kg.…”

Latest updates on the serotonergic system in depression and anxiety

“…Recent studies have demonstrated the antidepressant and anxiolytic effects of two specific 5-HT6 receptor agonists in rodents (Carr et al, 2011 ). The 5-HT6 receptor agonists enhanced the effects of haloperidol and reduced the haloperidol-induced side effects (Wesołowska et al, 2021 ). Furthermore, 5-HT6 receptor antagonists such as SB-399885 have been shown to have antidepressant effects in animal studies.…”

“…Paradoxical results are explained by the specific modulation of cerebral neurocircuits by different 5-HT6 receptor agonists or antagonists. Further studies are needed to clarify the brain region specificity of 5-HT6 receptors and their implication in depression (Wesołowska et al, 2021 ).…”