Role of 5-HT3 Receptors in the Antidepressant Response

Bétry, Cécile; Etiévant, Adeline; Oosterhof, Chris; Ebert, Bjarke; Sanchéz, Connie; Haddjeri, Nasser

doi:10.3390/ph4040603

Cited by 62 publications

(46 citation statements)

References 198 publications

(276 reference statements)

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“…The 5-HT 3 receptor is the only pentameric ligand-gated cation channel of the 5-HT receptor family. Preclinical and clinical studies suggest that 5-HT 3 receptor antagonists may have antidepressant activity since they present antidepressant-like properties in preclinical tests (for review Bétry et al, 2011) and have also shown antidepressant and anxiolytic properties in humans (Lecrubier et al, 1993;McCann et al, 1997;Johnson et al, 2003;Piche et al, 2005;Harmer et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

A 5-HT3 receptor antagonist potentiates the behavioral, neurochemical and electrophysiological actions of an SSRI antidepressant

Bétry

Overstreet

Haddjeri

et al. 2015

Pharmacology Biochemistry and Behavior

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Section: Introductionmentioning

confidence: 99%

A 5-HT3 receptor antagonist potentiates the behavioral, neurochemical and electrophysiological actions of an SSRI antidepressant

Bétry

Overstreet

Haddjeri

et al. 2015

Pharmacology Biochemistry and Behavior

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“…It is worth mentioning that an important drug used for the clinical treatment of anxiety and depression, buspirone, is a full agonist of presynaptic and a partial agonist of postsynaptic 5-HT 1A receptors (Butkevich et al 2011). In addition, clinical and preclinical studies have suggested that 5-HT 3 receptors may be a relevant target in the treatment of affective disorders (Bétry et al 2011). Lastly, hippocampal MAO A and/or B activity as well as 5-HT 2A/2C receptors seem not be involved in the antidepressant-like action of (p-ClPhSe) 2 .…”

Section: Discussionmentioning

confidence: 99%

p-Chloro-diphenyl diselenide, an organoselenium compound, with antidepressant-like and memory enhancer actions in aging male rats

et al. 2011

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The aim of this study was to evaluate the protective effects of p-chloro-diphenyl diselenide (p-ClPhSe)(2) on depressant-like action and cognitive impairment caused by aging in male rats. For this purpose, old rats were orally treated with (p-ClPhSe)(2) (10 or 25 mg/kg) for seven days. Then, rats were tested in experimental models of ambulation, memory and depression. In addition, Na(+) K(+) ATPase activity and reactive species (RS) levels were measured in rat cortex and hippocampus. Our findings demonstrated that treatment of old rats with (p-ClPhSe)(2) (10 and 25 mg/kg) reversed spatial memory deficit in the object location test and depressant-like action in the forced swimming test (FST) caused by aging. Reduction in exploratory behavior (rearings) in the open-field test caused by aging was not altered by (p-ClPhSe)(2) administration. Moreover, the increase of RS levels and inhibition of Na(+) K(+) ATPase activity in cortex and hippocampus resulting from aging were restored by the highest dose of (p-ClPhSe)(2). To assess the mechanisms involved in the antidepressant-like effect of (p-ClPhSe)(2), old rats received WAY100635 (0.1 mg/kg, subcutaneous, a selective 5-HT(1A)R antagonist), ritanserin (1 mg/kg, intraperitoneal, a 5-HT(2A/2C)R antagonist) or ondansetron (1 mg/kg, intraperitoneal, a 5-HT(3)R antagonist) 15 min before (p-ClPhSe)(2) (25 mg/kg) treatment. After 30 min, the FST was performed. Results showed that in addition to the antioxidant action, the modulation of 5-HT(1A) and 5-HT(3) receptors may be at least partly involved in the antidepressant-like action elicited by (p-ClPhSe)(2) in old rats. These findings highlight the beneficial potential of (p-ClPhSe)(2) in aged male rats.

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“…5-HT 3 R antagonists are used to effectively treat patients experiencing irritable bowel syndrome and chemotherapy-/radiotherapy-induced and postoperative nausea and vomiting (Thompson, 2007). Some antidepressants (Choi, 2003; Eisensamer, 2003) and antipsychotic drugs (Rammes, 2004) also antagonize 5-HT 3 R, which, together with other preclinical and clinical studies, suggest the relevance of 5-HT 3 R antagonism for treating psychiatric disorders (Bétry, 2011). We recently discovered that bupropion, another antidepressant, antagonizes 5-HT 3A R (Pandhare, 2017).…”

Section: Introductionmentioning

confidence: 89%

Bupropion inhibits serotonin type 3AB heteromeric channels at a physiologically relevant concentration

Stuebler

Jansen

2019

Preprint

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Bupropion, a FDA-approved antidepressant and smoking cessation aid, blocks dopamine and norepinephrine reuptake transporters and non-competitively inhibits nicotinic acetylcholine (nACh) and serotonin type 3A (5-HT 3 ) receptors. 5-HT 3 receptors are pentameric ligand-gated ion channels that regulate synaptic activity in the central and peripheral nervous system pre-and postsynaptically. In the present study, we examined and compared the effect of bupropion and its active metabolite hydroxybupropion on homomeric 5-HT 3A and heteromeric mouse 5-HT 3AB receptors expressed in Xenopus laevis oocytes using two-electrode voltage clamp experiments. Co-application of bupropion or hydroxybupropion with 5-HT dose-dependently inhibited 5-HT-induced currents in 5-HT 3AB Rs (IC 50 = 866 μ M and 505 μ M, respectively) but potentiated 5-HT-induced currents at low (30-50 μ M) concentrations. The corresponding IC 50 s for bupropion and hydroxybupropion with 5-HT 3A R were 10-and 5-fold lower, respectively (87 μ M and 113 μ M), and no potentiation was observed. The inhibition of 5-HT 3A R and 5-HT 3AB R was non-use dependent and voltage-independent, indicating bupropion is not an open channel blocker. The inhibition by bupropion was reversible and time-dependent. Of note, pre-incubation with a low concentration of bupropion that mimics therapeutic drug conditions significantly inhibited 5-HT induced currents in 5-HT 3A and even more so 5-HT 3AB receptors. In summary, our results indicate that bupropion inhibits 5-HT 3AB R, as well as homomeric receptors, and that this inhibition takes place at clinically-relevant concentrations. Inhibition of 5-HT 3 receptors by bupropion may contribute to its desired and/or undesired clinical effects. Significance Statement5-HT 3AB receptors are found in brain areas involved in mood regulation. Clinical studies indicate that antagonizing these receptors was successful in treating mood and anxiety disorders. Some currently clinically available antidepressants and antipsychotics act as antagonists of 5-HT 3 receptors. Previously, bupropion was shown to be an antagonist at homopentameric 5-HT 3A receptors. The present work provides novel insights into the pharmacological effects bupropion exerts on heteromeric 5-HT 3AB receptors. The results advance the knowledge on the clinical effect of bupropion as an antidepressant. the functional responses observed in native tissues (Davies, 1999; Dubin, 1999; Hussy, 1994; Maricq, 1991). When compared to 5-HT 3A R, 5-HT 3AB R differs in agonist concentration-response curves, shows increased single-channel conductance and desensitization, and an altered current-voltage relationship (Davies, 1999; Dubin, 1999; Kelley, 2003b; Thompson, 2013).The 5-HT 3 R is widely distributed in the central and peripheral nervous systems, and on extraneuronal cells, such as monocytes, chondrocytes, T-cells, and synovial tissue (Fiebich, 2004). In the periphery, 5-HT 3 Rs are found in the autonomic, sensory and enteric nervous systems (Faerber, 2007) where they are involved in...

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Role of 5-HT3 Receptors in the Antidepressant Response

Cited by 62 publications

References 198 publications

A 5-HT3 receptor antagonist potentiates the behavioral, neurochemical and electrophysiological actions of an SSRI antidepressant

A 5-HT3 receptor antagonist potentiates the behavioral, neurochemical and electrophysiological actions of an SSRI antidepressant

p-Chloro-diphenyl diselenide, an organoselenium compound, with antidepressant-like and memory enhancer actions in aging male rats

Bupropion inhibits serotonin type 3AB heteromeric channels at a physiologically relevant concentration

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