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-HT_1B receptors has been hypothesized to attain an important role. Objectives: To evaluate the role of endogenous stimulation of 5-HT_1B 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-HT_1B 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-HT_1B receptor activation during testing appears to be critical for S-ketamine's antidepressant-like potentials in this model.

Keywords: 5-HT); 5-HT1B receptors; CP94253; antidepressants; forced swim test; ketamine; serotonin (5-hydroxytryptamine.

FIGURE 1

Experimental design and treatment groups. CP9, CP94253; KET, S-ketamine.

FIGURE 2

Coronal slices outlining the striatum at 1.5–1.2 mm anterior to Bregma were used for 5-HT_1B receptor occupancy assessments. These brain slices represent total (left) and non-specific binding (right). This region exhibited a high degree of specific binding.

FIGURE 3

CP94253 displayed antidepressant-like activity in the FST. Vehicle-pretreated FSL control rats displayed a significantly higher immobility (A) as well as lower swimming (B) and climbing (C) behavior compared to FRL controls. pCPA pretreatment did not affect the behavior of FSL rats. When administered 2 h prior to the FST, CP94253 reduced immobility and enhanced climbing in 5-HT depleted FSL rats with a minimum effective dose of 6 mg/kg. Asterisks represent significant differences from vehicle-pretreated FSL control rats (^∗∗∗p < 0.001). Plus signs represent significant differences from pCPA-pretreated FSL control rats (⁺⁺p < 0.01; ⁺⁺⁺p < 0.001). Values are mean ± SEM. The number of animals (n) is shown in each column. ˆ Data previously published in du Jardin et al. (2016).

FIGURE 4

The acute antidepressant-like effects of S-ketamine were abolished by 5-HT depletion but rescued by the 5-HT_1B receptor agonist CP94253. In the FST, vehicle-pretreated FSL control rats displayed a significantly higher immobility (A) as well as lower swimming (B) and climbing (C) behavior compared to FRL controls. These behaviors were not affected by pCPA pretreatment. S-ketamine administration at 2 h before the FST decreased immobility and increased swimming in vehicle- but not pCPA-pretreated FSL rats. Supplementing this regimen with a 5-HT_1B receptor agonist 2 h prior to testing reduced immobility as well as increased swimming and climbing behavior relative to 5-HT depleted FSL control rats. Asterisks represent significant differences from vehicle-pretreated FSL control rats (^∗∗∗p < 0.001). Plus signs represent significant differences from pCPA-pretreated FSL control rats (⁺p < 0.05; ⁺⁺⁺p < 0.001). Values are mean ± SEM. The number of animals (n) is shown in each column. ˆ Data previously published in du Jardin et al. (2016).

FIGURE 5

The sustained antidepressant-like effects of S-ketamine were abolished by 5-HT depletion but rescued by the 5-HT_1B receptor agonist, CP94253. In the FST, vehicle-pretreated FSL control rats displayed significantly higher immobility (A) as well as lower swimming (B) and climbing (C) behavior compared to FRL controls. 5-HT depletion did not affect the behavior of FSL control rats. In vehicle-pretreated FSL rats, S-ketamine administration at 48 h prior to the FST reduced immobility and increased swimming. These effects were abolished by pCPA pretreatment and restored by co-treatment with a 5-HT_1B receptor agonist at 2 h, but not 49 h, prior to testing. Asterisks represent significant differences from vehicle-pretreated FSL control rats (^∗∗∗p < 0.001). Plus signs represent significant differences from pCPA-pretreated FSL control rats (⁺⁺p < 0.01; ⁺⁺⁺p < 0.001). Values are mean ± SEM. The number of animals (n) is shown in each column. ˆ Data previously published in du Jardin et al. (2016).