NLRP1-Mediated Antidepressant Effect of Ketamine in Chronic Unpredictable Mild Stress Model in Rats

Abstract

Objective NOD-like receptor protein 1 (NLRP1) inflammasome complex has been recently associated with chronic unpredictable mild stress (CUMS) model of depression. Our aim was to investigate whether ketamine-induced antidepressant effect is associated with suppression of NLRP1.Methods Wistar albino rats were divided into control, CUMS, CUMS+acute ketamine (a single 10 mg/kg dose) and CUMS+chronic ketamine (daily 10 mg/kg injections for 3 weeks) groups (n=10 for each group). Sucrose preference test and forced swimming test were performed to assess anhedonia and immobility time respectively for the severety of depression symptoms. Brain tissues were dissected and prefrontal cortex and hippocampus regions were used for real-time polymerase chain reaction (PCR) and immunohistochemical analysis.Results CUMS procedure significantly induced depressive-like symptoms whereas both acute and chronic ketamine treatment ameliorated them. mRNA expression levels of NLRP1, caspase 1, apoptosis-associated speck-like protein containing a CARD (ASC), NF-κB, endothelial nitric oxide synthase, IL-1β, IL-6, toll-like receptor 4 (TLR-4) and purinergic 2×7 receptor (P2X7R) and numbers of Iba- 1+and GFAP+glial cells were reduced by acute and/or chronic ketamine treatment.Conclusion In the present study for the first time upstream and downstream elements of the NLRP1 inflammasome complex are shown to be suppressed by ketamine thus reinforcing the involvement of NLRP1 in the physiopathology of depression.

Repeated Dosing of Ketamine in the Forced Swim Test: Are Multiple Shots Better Than One?

“…For example, studies such as Clarke et al (40) and Neves et al (42), which directly compare in mice a single injection vs. multiple injections at the same dose, suggest that the immobility decreasing effects of repeated ketamine may last longer than those of one injection. Another point is that repeated dosing regimens are capable of producing a decrease in immobility when ketamine is given at different fixed intervals, including less frequently than once a day (40,41,49), exactly once a day (39,42,49,50,52,53,(58)(59)(60), or twice a day (36). In Sprague-Dawley rats weekly administration of ketamine, for 5 weeks at 20 or 50 mg/kg, has previously been shown to induce locomotor sensitization (66).…”

“…Inspection of Table 1 also reveals that not many studies of repeated ketamine have used chronic stress, even though as described earlier chronic stress or trauma is an etiological factor in human MDD ( 26 , 27 ). While we identified only four studies (all carried out in rats) that used chronic stress in Table 1 , in each of the experiments carried out there was a decrease in immobility, after either a single injection or multiple injections, that was statistically significant in most cases and lasted up to 2 months for repeated injections ( 36 , 49 , 50 , 58 ). These daily unpredictable stress procedures varied in length from 15 ( 36 ) to 42 days ( 50 , 58 ), and used either one ( 58 ) or two ( 36 , 49 , 50 ) stressors per day, such as cage tilting or placing wet bedding in the cage.…”

“…While we identified only four studies (all carried out in rats) that used chronic stress in Table 1 , in each of the experiments carried out there was a decrease in immobility, after either a single injection or multiple injections, that was statistically significant in most cases and lasted up to 2 months for repeated injections ( 36 , 49 , 50 , 58 ). These daily unpredictable stress procedures varied in length from 15 ( 36 ) to 42 days ( 50 , 58 ), and used either one ( 58 ) or two ( 36 , 49 , 50 ) stressors per day, such as cage tilting or placing wet bedding in the cage. These behavioral findings after chronic stress was administered are consistent with experiments from our laboratory that used C57BL/6J mice, and found that chronic stress was either necessary for ( 28 ) or amplified ( 29 ) the increases in swimming or decreases in immobility produced by a single injection of ketamine.…”

“…Whether repeated use of lower doses is more effective at reducing immobility than a single administration of that same dose or a different one, seems to be unclear at this time. Some studies that used both single and repeated injections show an advantage for chronic dosing over a single dose ( 40 , 42 , 58 ), whereas others show the opposite pattern ( 47 , 54 ) or no clear advantage for either dosing regimen ( 41 ). The Chindo et al ( 54 ) and Hou et al ( 47 ) studies found immobility increasing effects of repeated ketamine at relatively high doses of this drug (30–100 mg/kg), which may suggest that repeated dosing can be more favorable than a single dose if a sufficiently low dose (such as 10 mg/kg or lower) is used repeatedly, or perhaps if there is a longer interval between administrations.…”

“…The Chindo et al ( 54 ) and Hou et al ( 47 ) studies found immobility increasing effects of repeated ketamine at relatively high doses of this drug (30–100 mg/kg), which may suggest that repeated dosing can be more favorable than a single dose if a sufficiently low dose (such as 10 mg/kg or lower) is used repeatedly, or perhaps if there is a longer interval between administrations. Beyond there being some degree of difference in dose used in these above five studies, it is difficult to draw further conclusions from them on the efficacy of repeated dosing due to different experimental parameters used, such as ( S )-ketamine ( 42 ) or chronic stress ( 58 ). In general, the scarcity of studies reviewed here that have used repeated ketamine in the FST precludes definitive conclusions on the potential interactions between variables such as strain, sex, stress, and dose.…”