Behavioural sensitization to repeated sleep deprivation in a mice model of mania

Sensitization to the effect of stress has been hypothesized as a mechanism to explain episode recurrence and cycle acceleration in bipolar disorder. Naturalistic observations and experimental work in human patients suggested that sleep deprivation can trigger manic episodes of illness. In rats sleep deprivation (SD) with the platform method caused mania-like behaviours thus providing an animal model of mania with face, construct, and predictive validity. In the present study we administered SD or control stress to male CD1 mice following a dose-response protocol based on time of exposure to the experimental conditions (6, 12 or 24 h) and repetition of treatment (three times). SD, but not stress-control conditions, increased motor activity and aggressive behaviours. The behavioural activation followed a dose-response curve based on length of treatment, with non-significant trends after 6h, significant effects after 12 h, and maximal effects after 24 h. Moreover, the behavioural activation followed a time-response curve, with progressive sensitization to the effects of SD, but not of control stress, upon its repetition. This is the first animal model of behavioural sensitization to the effects of a specific stress (sleep deprivation) known to trigger mania in bipolar patients. We expect it to be useful to test the efficacy of antimanic and mood-stabilizer drugs, and to study the neurobiological correlates of manic reactions in order to gain new insight into the pathophysiology of bipolar illness and to identify new targets for treatment.