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Recently there is increasing concern over the association between sleep deprivation (S-Dep) and depression. Mounting evidence suggests that S-Dep might be a risk factor for depression. However, underlying molecular mechanism remains elusive and currently there is no effective therapy to negate the effects of S-Dep. In this study, we aimed to examine whether subchronic treatment of citalopram (CTM), an antidepressant, can attenuate the negative effects of S-Dep in mice. Three-month-old C57BL/6J mice were divided into control, S-Dep, CTM control and CTM + S-Dep groups. CTM and CTM + S-Dep group treated with citalopram for 5 consecutive days at a dose of 10 mg/kg per day before experimental procedure. S-Dep and CTM + S-Dep group mice were sleep deprived for 24 h using an automated treadmill method. Our results revealed that S-Dep animals displayed an increased depressive-like behavior in forced swim, tail suspension and sucrose preference test and anxiety-like behavior in the open field and elevated plus maze, as well as disrupted spatial memory in Morris water maze. Western blotting analysis revealed that S-Dep caused reductions in the levels of the plasticity- and memory-related signaling molecules i.e. pCaMKII and pCREB in the hippocampus. Moreover, S-Dep animals showed synaptic plasticity deficits in the Schaffer collateral pathway. Interestingly, subchronic CTM treatment prevented S-Dep-induced decrease in pCaMKII and pCREB levels in the hippocampus. Furthermore, CTM treatment prevented S-Dep-induced deficits in synaptic plasticity, spatial memory, depressive-like behavior in sucrose preference test and anxiety-like behavior in open field test but not in force swim, tail suspension and elevated plus maze test. This data suggests differential effects of CTM on S-Dep-associated behavioral alterations and cognitive impairments.Sleep deprivation induces depressive-like behavior in mice.Sleep deprivation causes reduction of pCaMKII and pCREB in hippocampus.Sleep deprivation disrupts hippocampal synaptic plasticity and spatial memory.Citalopram prevents sleep-deprivation-induced reduction in pCaMKII and pCREB levels.Citalopram prevents synaptic plasticity deficits, memory impairments and most of the behavioral alterations.