Dexmedetomidine potently and reversibly regulates stress-mediated behaviors.

Aims: Demonstrate that dexmedetomidine is potentially useful for treatment of psychiatric symptoms caused by acute or chronic stress by using relevant rodent models and doses predicted to achieve sufficient brain levels to activate alpha2-adrenoceptors. Methods: Results: Dexmedetomidine is both more potent (<10 nM EC50) and has higher intrinsic activity than other α2-AR agonists (clonidine, lofexidine or guanfacine). Estimates of free brain levels at efficacious doses are sufficient to activate all 3 α2-ARs. Dexmedetomidine was effective in decreasing immobility (increasing escape behaviors) in the forced swim test after a single acute stress and in the open space swim test after repeat dosing. Effects of dexmedetomidine were completely reversible and no withdrawal effects were observed. Doses used in the open space swim test had no overt effect on the rotarod indicating no impairment of motor coordination. Dexmedetomidine was highly effective in reversing a CCK-4 induced mediated deficit in the elevated plus maze, a translatable model for anxiety and panic. Dexmedetomidine also increased latency to REM sleep and shortened latency to slow wave sleep, positive attributes for a neuropsychiatric drug. Conclusion: Dexmedetomidine may be a suitable drug for a chronic dosing for a wide range of stress-mediated symptoms, not limited to the acute treatment of agitation. Brain levels are highly predictable based on plasma exposures and are consistent with the known affinity for α2-ARs.