Sex and circadian-dependent modulation of ketamine's rapid behavioural effects in a Mouse Model of Chronic Restraint Stress

Major depressive disorder (MDD) is a highly debilitating psychiatric disorder with increasing incidence worldwide. In addition to its effects on the central nervous system, MDD is associated with systemic, metabolic and tissue-specific changes. Chronic stress is recognised as a major risk factor for the development of neuropsychiatric disorders, and thus rodent models of depression typically involve exposure to stress. Other contributors to the heterogeneity of depressive disorders include biological sex and circadian disruption, both of which increase clinical variability. This study also considers the effects of ketamine, a fast-acting antidepressant. In animal models. A single subanesthetic intraperitoneal dose of racemic ketamine (10 mg/kg) has been shown to reverse stress-induced reductions in dendritic arborisation and synaptic spine density within corticolimbic regions within 24 hours. However, the exact mechanisms underlying these effects remain unclear. The aim of this study was to evaluate the modulation of ketamine's rapid behavioural effects to a chronic restraint stress protocol (21 days, 2 hours/day) in male and female mice subjected to stress under either light or dark conditions. Depressive-like symptoms were assessed using various behavioural tests such as tail suspension, open field, splash and forced swim test. The results indicate that both sex and circadian disruption significantly influence the development of depressive-like behaviours. Female mice showed more severe behavioural impairment than males. In addition, stress applied during the light phase was more effective in inducing depressive-like states than stress applied during the dark phase. Ketamine treatment resulted in significant improvements in behavioural parameters in all conditions, confirming its antidepressant efficacy. These results suggest that sex and circadian rhythm are critical variables in the onset and expression of depressive-like phenotypes in mice and may influence the effectiveness of therapeutic interventions such as ketamine