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.
Highlights
Hours after a single i.v., infusion of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine, patients with refractory major depressive disorder may experience a remarkable mood improvement (Berman et al, 2000)
After pCPA pretreatment 5-hydroxyindole acetic acid (5-HIAA) levels were below the detection limit and no data on 5-HIAA or 5-HT turnover are presented for these treatment groups
5-HT1B Occupancy after CP94253 Dosing In Flinders sensitive line (FSL) rats pretreated with pCPA, a single dose of 1, 3, and 6 mg/kg CP94253 at 2 h prior to euthanization resulted in a 5-HT1B receptor occupancy of 45.1 ± 8.8, 75.0 ± 4.3, and 84.5 ± 0.5%, respectively, (n = 3 for all groups)
Summary
Hours after a single i.v., infusion of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine, patients with refractory major depressive disorder may experience a remarkable mood improvement (Berman et al, 2000) This rapid onset of antidepressant action is unlike the delayed effects of current-first line antidepressants, which require in the order of weeks to provide clinical efficacy. Our group as well as others have shown that ketamine’s antidepressant-like activity in the forced swim test (FST) is abolished by serotonin [5-hydroxytryptamine (5-HT)] depletion induced by the irreversible tryptophan hydroxylase inhibitor 4-chloro-DL-phenylalanine methyl ester HCl (pCPA), which blocks the rate-limiting step of 5-HT synthesis (Gigliucci et al, 2013; Fukumoto et al, 2015; du Jardin et al, 2016) These data indicate that ketamine elicits its antidepressant-like actions via a 5-HT-dependent mechanism. The 5-HT1A (Fukumoto et al, 2014), 5-HT2 (Fukumoto et al, 2014), and 5-HT3 (Kos et al, 2006) receptor subtypes have been sparsely investigated in the context of ketamine’s antidepressantlike actions, but with limited indication that these receptor subtypes are implicated in the antidepressant-like effect
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