Traumatic brain injury (TBI) is a frequent cause of chronic headache, fatigue, insomnia, hyperactivity, memory deficits, irritability and posttraumatic stress disorder. Recent evidence suggests beneficial effects of pro-cannabinoid treatments. We assessed in mice levels of endocannabinoids in association with the occurrence and persistence of comparable sequelae after controlled cortical impact in mice using a set of long-term behavioral observations in IntelliCages, motor and nociception tests in two sequential cohorts of TBI/sham mice. TBI mice maintained lower body weights, and they had persistent low levels of brain ethanolamide endocannabinoids (eCBs: AEA, OEA, PEA) in perilesional and subcortical ipsilateral brain tissue (6 months), but rapidly recovered motor functions (within days), and average nociceptive responses were within normal limits, albeit with high variability, ranging from loss of thermal sensation to hypersensitivity. TBI mice showed persistent non-goal directed nighttime hyperactivity, i.e. they visited rewarding and non-rewarding operant corners with high frequency and random success. On successful visits, they made more licks than sham mice resulting in net over-licking. The lower the eCBs the stronger was the hyperactivity. In reward-based learning and reversal learning tasks, TBI mice were not inferior to sham mice, but avoidance memory was less stable. Hence, the major late behavioral TBI phenotype was non-goal directed nighttime hyperactivity and "over-licking" in association with low ipsilateral brain eCBs. The behavioral phenotype would agree with a "post-TBI hyperactivity disorder". The association with persistently low eCBs in perilesional and subcortical regions suggests that eCB deficiency contribute to the post-TBI psychopathology.

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