Connie Sánchez

S-Ketamine Mediates Its Acute and Sustained Antidepressant-Like Activity through a 5-HT1B Receptor Dependent Mechanism in a Genetic Rat Model of Depression

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S-Ketamine Mediates Its Acute and Sustained Antidepressant-Like Activity through a 5-HT1B Receptor Dependent Mechanism in a Genetic Rat Model of Depression. / du Jardin, Kristian G; Liebenberg, Nico; Cajina, Manuel; Müller, Heidi K; Elfving, Betina; Sanchez, Connie; Wegener, Gregers.

In: Frontiers in Pharmacology, Vol. 8, 2017, p. 978.

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@article{bfabc4a2381c4150ba86275786ffcab4,
title = "S-Ketamine Mediates Its Acute and Sustained Antidepressant-Like Activity through a 5-HT1B Receptor Dependent Mechanism in a Genetic Rat Model of Depression",
abstract = "Rationale: The mechanisms responsible for the unique antidepressant properties of ketamine have only been partly resolved. Recent preclinical reports implicate the neurotransmitter serotonin [5-hydroxytryptamine (5-HT)] in the antidepressant-like response of ketamine, and modulation of 5-HT1B receptors has been hypothesized to attain an important role. Objectives: To evaluate the role of endogenous stimulation of 5-HT1B heteroreceptors in the antidepressant-like activity of S-ketamine. Method: Flinders sensitive line (FSL) rats, a genetic model of depression, were depleted of endogenous 5-HT by 4-chloro-DL-phenylalanine methyl ester HCl administration (pCPA; 86 mg/kg/day for 3 days). In pCPA-pretreated and control FSL rats, the acute and sustained effects of a single dose of S-ketamine (15 mg/kg) and the selective 5-HT1B receptor agonist CP94253 (1-6 mg/kg) alone and in combination with S-ketamine were studied in the forced swim test (FST), a commonly used assay that detects antidepressant activity. Results: pCPA pretreatment decreased cortical 5-HT levels to ∼6% but did not affect the baseline behavioral phenotype of FSL rats. S-ketamine demonstrated acute and sustained antidepressant-like activity, both of which were abolished by 5-HT depletion. Combining S-ketamine with a sub-effective dose of CP94253 (1 mg/kg) rescued S-ketamine's acute and sustained antidepressant-like effects, when CP94253 was administered 2 h prior to the FST. Co-administration of S-ketamine and CP94253 did not affect the plasma level of either compound, suggesting that the observed behavioral interaction could not be ascribed to a kinetic drug-drug interaction. Conclusion: 5-HT1B receptor activation during testing appears to be critical for S-ketamine's antidepressant-like potentials in this model.",
keywords = "Journal Article",
author = "{du Jardin}, {Kristian G} and Nico Liebenberg and Manuel Cajina and M{\"u}ller, {Heidi K} and Betina Elfving and Connie Sanchez and Gregers Wegener",
year = "2017",
doi = "10.3389/fphar.2017.00978",
language = "English",
volume = "8",
pages = "978",
journal = "Frontiers in Pharmacology",
issn = "1663-9812",
publisher = "Frontiers Research Foundation",

}

RIS

TY - JOUR

T1 - S-Ketamine Mediates Its Acute and Sustained Antidepressant-Like Activity through a 5-HT1B Receptor Dependent Mechanism in a Genetic Rat Model of Depression

AU - du Jardin, Kristian G

AU - Liebenberg, Nico

AU - Cajina, Manuel

AU - Müller, Heidi K

AU - Elfving, Betina

AU - Sanchez, Connie

AU - Wegener, Gregers

PY - 2017

Y1 - 2017

N2 - Rationale: The mechanisms responsible for the unique antidepressant properties of ketamine have only been partly resolved. Recent preclinical reports implicate the neurotransmitter serotonin [5-hydroxytryptamine (5-HT)] in the antidepressant-like response of ketamine, and modulation of 5-HT1B receptors has been hypothesized to attain an important role. Objectives: To evaluate the role of endogenous stimulation of 5-HT1B heteroreceptors in the antidepressant-like activity of S-ketamine. Method: Flinders sensitive line (FSL) rats, a genetic model of depression, were depleted of endogenous 5-HT by 4-chloro-DL-phenylalanine methyl ester HCl administration (pCPA; 86 mg/kg/day for 3 days). In pCPA-pretreated and control FSL rats, the acute and sustained effects of a single dose of S-ketamine (15 mg/kg) and the selective 5-HT1B receptor agonist CP94253 (1-6 mg/kg) alone and in combination with S-ketamine were studied in the forced swim test (FST), a commonly used assay that detects antidepressant activity. Results: pCPA pretreatment decreased cortical 5-HT levels to ∼6% but did not affect the baseline behavioral phenotype of FSL rats. S-ketamine demonstrated acute and sustained antidepressant-like activity, both of which were abolished by 5-HT depletion. Combining S-ketamine with a sub-effective dose of CP94253 (1 mg/kg) rescued S-ketamine's acute and sustained antidepressant-like effects, when CP94253 was administered 2 h prior to the FST. Co-administration of S-ketamine and CP94253 did not affect the plasma level of either compound, suggesting that the observed behavioral interaction could not be ascribed to a kinetic drug-drug interaction. Conclusion: 5-HT1B receptor activation during testing appears to be critical for S-ketamine's antidepressant-like potentials in this model.

AB - Rationale: The mechanisms responsible for the unique antidepressant properties of ketamine have only been partly resolved. Recent preclinical reports implicate the neurotransmitter serotonin [5-hydroxytryptamine (5-HT)] in the antidepressant-like response of ketamine, and modulation of 5-HT1B receptors has been hypothesized to attain an important role. Objectives: To evaluate the role of endogenous stimulation of 5-HT1B heteroreceptors in the antidepressant-like activity of S-ketamine. Method: Flinders sensitive line (FSL) rats, a genetic model of depression, were depleted of endogenous 5-HT by 4-chloro-DL-phenylalanine methyl ester HCl administration (pCPA; 86 mg/kg/day for 3 days). In pCPA-pretreated and control FSL rats, the acute and sustained effects of a single dose of S-ketamine (15 mg/kg) and the selective 5-HT1B receptor agonist CP94253 (1-6 mg/kg) alone and in combination with S-ketamine were studied in the forced swim test (FST), a commonly used assay that detects antidepressant activity. Results: pCPA pretreatment decreased cortical 5-HT levels to ∼6% but did not affect the baseline behavioral phenotype of FSL rats. S-ketamine demonstrated acute and sustained antidepressant-like activity, both of which were abolished by 5-HT depletion. Combining S-ketamine with a sub-effective dose of CP94253 (1 mg/kg) rescued S-ketamine's acute and sustained antidepressant-like effects, when CP94253 was administered 2 h prior to the FST. Co-administration of S-ketamine and CP94253 did not affect the plasma level of either compound, suggesting that the observed behavioral interaction could not be ascribed to a kinetic drug-drug interaction. Conclusion: 5-HT1B receptor activation during testing appears to be critical for S-ketamine's antidepressant-like potentials in this model.

KW - Journal Article

U2 - 10.3389/fphar.2017.00978

DO - 10.3389/fphar.2017.00978

M3 - Journal article

C2 - 29379439

VL - 8

SP - 978

JO - Frontiers in Pharmacology

JF - Frontiers in Pharmacology

SN - 1663-9812

ER -