Agonist E-6837 and antagonist SB-271046 of 5-HT6 receptors both reverse the depressive-like effect induced in mice by subchronic ketamine administration

Abstract

Major depression is one of the most common affective disorders caused by schizophrenia. The administration of N-methyl-D-aspartate receptor antagonists, such as ketamine, can reproduce the negative and affective symptoms of this disorder in animals. Preclinical studies have shown that 5-HT6 receptor (5-HT6R) agonists and antagonists have a considerable antipsychotic response. The aim of the present study was to evaluate the effect of an acute treatment with an agonist, E-6837, and an antagonist, SB-271046, of 5-HT6R on the immobility induced in mice by a subchronic ketamine regimen (5 days; 10 mg/kg/day, intraperitoneal). Repeated ketamine administration alone increased the immobility time in the forced-swimming test and the tail-suspension test. E-6837 at 10 and 20 mg/kg caused a significant reduction of immobility in the tail-suspension test and forced-swimming test, respectively. Interestingly, SB-271046 (10 mg/kg) also elicited an antidepressant-like effect in both tests. The current findings suggest an important role for these 5-HT6R ligands as mood modulators. However, it is necessary to explore the physiological mechanisms involved in this process in greater detail.

Stress-sensitive antidepressant-like effects of ketamine in the mouse forced swim test

“…A number of the published ketamine and stress studies do not report data on ketamine in unstressed controls (for example: [35,36]), and if this had been done more frequently, perhaps the current findings would already be established in C57BL/6J mice. It should also be pointed out that a recent study in unstressed male NIH mice found that subchronic (5 days) administration of 10 mg/kg ketamine, increased immobility time in the FST and tail suspension test [37]; however the repeated administration of drug in that study may modulate locomotor activity, which precludes direct comparison with our single injection findings in unstressed mice. It has already been noted by others that both the strain and stress state of the animal may affect antidepressant-like responses to ketamine, where using animals exhibiting depression-like behavior (rather than only unstressed ones) may be critical in investigating affective-like behavioral responses to ketamine [38].…”

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

“…While we have previously suggested ( 14 ) that the field has converged on using 10 mg/kg as a standard dose in single injection rodent FST experiments ( 16 ), our own data have suggested that 30 mg/kg is more effective at reducing immobility in male C57BL/6J mice ( 28 ). A repeated dose as low as 10 mg/kg in Table 1 has actually been associated with increases in immobility in mice ( 38 , 39 , 55 ). The field has not converged on a single repeated dose found to be generally efficacious in all labs and contradictory results are frequent.…”

“…For all of these reasons, future rodent studies aimed at investigating the putative antidepressant properties of ketamine (or other drugs) should consider including a battery of other behavioral tests [sucrose preference, novelty suppressed feeding, splash; as well as open field (to test generalized hyperactivity)] in addition to the FST. Repeated ketamine administration is only beginning to be investigated in these other tests (36)(37)(38).…”

The Anxiolytic Potential of a New Series of Diazepinobenzimidazole Derivatives

“…Многие препараты, помимо низкой эффективности, обладают выраженными побочными действиями -привыканием, вялостью, сонливостью и т.п. В настоящее вре-мя активно ведется поиск новых веществ с противотревожной активностью и низким риском развития побочных эффектов среди производных многих классов соединений, действующих на различные звенья патологического процесса [3,10]. Разрабатываются новые фармакологические подходы для решения сложной проблемы снижения патологической тревожности [9].…”