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| Content Provider | frontiers |
|---|---|
| Author | du Jardin, Kristian G. Liebenberg, Nico Cajina, Manuel Müller, Heidi K. Elfving, Betina Sanchez, Connie Wegener, Gregers |
| 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 postsynaptic 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 hr 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. Conclusions:5-HT1B receptor activation during testing appears to be critical for S-ketamine’s antidepressant-like potentials in this model. |
| ISSN | 16639812 |
| DOI | 10.3389/fphar.2017.00978 |
| Volume Number | 8 |
| Journal | Frontiers in Pharmacology |
| Language | English |
| Publisher Date | 2018-01-15 |
| Access Restriction | Open |
| Subject Keyword | Serotonin (5-hydroxytryptamine Antidepressants Forced swim test 5-HT1B receptors Ketamine 5-HT) CP94253 forced swim test |
| Content Type | Text |
| Resource Type | Article |
| Subject | Pharmacology Pharmacology (medical) |
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