Antidepressant and anxiolytic effects of selective 5-HT6 receptor agonists in rats

Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA.
Psychopharmacology (Impact Factor: 3.88). 03/2010; 213(2-3):499-507. DOI: 10.1007/s00213-010-1798-7
Source: PubMed


Although selective serotonin reuptake inhibitors (SSRIs) produce clinical therapeutic effects on depression and anxiety through augmentation of serotonergic neurotransmission, there is little known about the potential contributions of the 5-HT(6) receptor in the treatment of mood disorders.
The aim of this study was to test the potential antidepressant-like and anxiolytic-like effects of the 5-HT(6) receptor agonists WAY-208466 and WAY-181187 using established behavioral tests in rats.
In order to determine if the 5-HT(6) receptor agonists possess antidepressant-like activity, rats were treated with WAY-208466 or WAY-181187 and tested in the modified rat forced swim test (FST). Also, the potential anxiolytic-like effects of WAY-208466 and WAY-181187 were measured using the defensive burying (DB) test and novelty-induced hypophagia (NIH) test.
WAY-208466 and WAY-181187 produced both antidepressant-like and anxiolytic-like effects. Both compounds decreased immobility and increased swimming behavior in the FST. The effects of the 5-HT(6) receptor agonists were similar to those seen after treatment with the SSRI fluoxetine. Both 5-HT(6) receptor agonists also decreased burying duration in the DB test, indicative of anxiolytic activity in the test. The anxiolytic effects of WAY-208466 were reproduced in the NIH test. Assessment of the anxiolytic effects of WAY-181187 in the NIH was confounded by alterations in home cage feeding behavior.
These findings suggest that 5-HT(6) receptor agonists may represent a new class of potential antidepressant and anxiolytic compounds and could possess a number of advantages over currently available treatments, including rapid onset of anxiolytic efficacy.

Download full-text


Available from: Irwin Lucki, Sep 23, 2014
  • Source
    • "treated mice for 30 min before examining their locomotion for 5 min . A possible explanation for the different results is that our experiments are strongly influenced by a novelty response together with regular locomotor activity , whereas the results from Carr et al . ( 2011 )"
    [Show abstract] [Hide abstract]
    ABSTRACT: Serotonin (5-HT) and its receptors play crucial roles in various aspects of mood and cognitive functions. However, the role of specific 5-HT receptors in these processes remains to be better understood. Here, we examined the effects of the selective and potent 5-HT6 agonist (WAY208466) on mood, anxiety and emotional learning in mice. Male C57Bl/6J mice were therefore tested in the forced swim test (FST), elevated plus-maze (EPM), and passive avoidance tests (PA), respectively. In a dose-response experiment, mice were treated intraperitoneally with WAY208466 at 3, 9, or 27 mg/kg and examined in an open field arena open field test (OFT) followed by the FST. 9 mg/kg of WAY208466 reduced immobility in the FST, without impairing the locomotion. Thus, the dose of 9 mg/kg was subsequently used for tests of anxiety and emotional learning. There was no significant effect of WAY208466 in the EPM. In the PA, mice were trained 30 min before the treatment with saline or WAY208466. Two separate sets of animals were used for short term memory (tested 1 h post-training) or long term memory (tested 24 h post-training). WAY208466 improved both short and long term memories, evaluated by the latency to enter the dark compartment, in the PA. The WAY208466-treated animals also showed more grooming and rearing in the light compartment. To better understand the molecular mechanisms and brain regions involved in the facilitation of emotional learning by WAY208466, we studied its effects on signal transduction and immediate early gene expression. WAY208466 increased the levels of phospho-Ser(845)-GluA1 and phospho-Ser(217/221)-MEK in the caudate-putamen. Levels of phospho-Thr(202/204)-Erk1/2 and the ratio mature BDNF/proBDNF were increased in the hippocampus. Moreover, WAY208466 increased c-fos in the hippocampus and Arc expression in both hippocampus and prefrontal cortex (PFC). The results indicate antidepressant efficacy and facilitation of emotional learning by 5-HT6 receptor agonism via mechanisms that promote neuronal plasticity in caudate putamen, hippocampus, and PFC.
    Full-text · Article · Sep 2015 · Frontiers in Pharmacology
  • Source
    • "Compounds with affinity for serotoninergic (5-HT 6 , 5-HT 7 ) and dopaminergic type 2 receptors (D 2 Rs) exhibit potential for the treatment of diverse central nervous system disorders, e.g., depression [1] [2], schizophrenia [3], as well as dementia [4] and Alzheimer disease [5]. Importantly, derivatives with mixed receptor binding profile, often called serotonin/dopamine modulators, may attenuate both negative, positive symptoms of schizophrenia, as well as improve cognitive deficits [6] [7]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: N-(4-Arylpiperazinoalkyl)acetamide derivatives of 1,3-and 3,7-dimethyl-1H-purine-2,6(3H,7H)-diones and their 5-HT Abstract: A series of N-(arylpiperazinyl)acetamide derivatives of 1,3-and 3,7-dimethyl-1H-purine-2,6(3H,7H)-dione was synthesized and biologically evaluated in in vitro competition binding experiments for serotonin 5-HT 6 , 5-HT 7 , and dopamine D 2 receptors. The structure-affinity relationships for this group of compounds allowed for determination of structural features responsible for receptor affinity. Among the investigated derivatives, compounds 5 and 12 with (2,3-dichlorophenyl)piperazine moiety were classified as potent dual 5-HT 6 /D 2 receptors ligands, whereas compound 4, with 4-(benzo[d]isothia-zol-3-yl)piperazine moiety, and compounds 8 and 15, with (2,3-dichlorophenyl)piperazine moiety, were classified as potent D 2 receptor ligands.
    Full-text · Article · Feb 2015 · Heterocyclic Communications
  • Source
    • "One of the brain areas relevant for the antidepressant-like effect of 5-HT6 receptor antagonists appears to be the hippocampus, since intrahippocampal administration of SB-258585, a selective 5-HT6 receptor antagonist, reduces immobility duration [36]. However, with respect to the role of 5-HT6 receptor in this antidepressant-like effect, dissimilar results exist in that 5-HT6 receptor agonist also demonstrates an antidepressant-like effect in the mouse TST [13] and in the rat FST [12]. Moreover, intrahippocampal administration of 5-HT6 receptor agonist, EMD386088, reduces immobility duration in the FST in rats, suggesting an anti-depressant-like effect, and this effect is blocked by systemic administration of the selective 5-HT6 receptor antagonist SB-399885 [37]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Electroconvulsive shock (ECS) induces not only an antidepressant effect but also adverse effects such as amnesia. One potential mechanism underlying both the antidepressant and amnesia effect of ECS may involve the regulation of serotonin (5-hydroxytryptamine) 6 (5-HT6) receptor, but less is known about the effects of acute ECS on the changes in 5-HT6 receptor expression in the hippocampus. In addition, as regulation of 5-HT receptor expression is influenced by the number of ECS treatment and by interval between ECS treatment and sacrifice, it is probable that magnitude and time-dependent changes in 5-HT6 receptor expression could be influenced by repeated ECS exposure. To explore this possibility, we observed and compared the changes of 5-HT6 receptor immunoreactivity (5-HT6 IR) in rat hippocampus at 1, 8, 24, or 72 h after the treatment with either a single ECS (acute ECS) or daily ECS for 10 days (chronic ECS). We found that acute ECS increased 5-HT6 IR in the CA1, CA3, and granule cell layer of hippocampus, reaching peak levels at 8 h and returning to basal levels 72 h later. The magnitude and time-dependent changes in 5-HT6 IR observed after acute ECS were not affected by chronic ECS. These results demonstrate that both acute and chronic ECS transiently increase the 5-HT6 IR in rat hippocampus, and suggest that the magnitude and time-dependent changes in 5-HT6 IR in the hippocampus appear not to be influenced by repeated ECS treatment.
    Full-text · Article · Sep 2014
Show more