Melatonin MT1/2 receptor stimulation reduces cortical overflow of cholecystokinin-like material in a model of anticipation of social defeat in the rat

The involvement of cholecystokinin (CCK) in the potential anxiolytic-like effects of melatonin and of the antitumor MT1/2 receptor agonist, S23478, was assessed by measuring the cortical outflow of CCK-like material (CCKLM) in a rat model of anticipation of social defeat. After repeated social defeats by a male Tryon Maze Dull (TMD) rat, Sprague–Dawley (SD) rats were implanted for microdialysis in the frontal cortex and placed in the same environment as for the defeated sessions, but no confrontation with the TMD rat was allowed. Anticipation of social defeat induced anxiety-like behaviors (immobility, ultrasonic vocalization, defensive postures) associated with a significant increase (~+90%) in cortical CCKLM outflow in SD rats. Acute pretreatment with melatonin (5 or 40 mg/kg i.p.) or S23478, at 5 mg/kg i.p., had no or only minor effects on anxiety-like behaviors and did not affect CCKLM overflow. In contrast, at 40 mg/kg i.p., S23478 significantly reduced the duration of immobility and vocalization as well as the cortical CCKLM overflow (–30%) in defeated SD rats, and both effects were prevented by the MT1/2 receptor antagonist S22153 (40 mg/kg i.p.). These data indicated that MT1/2 receptor stimulation can exert anxiolytic-like effects associated with inhibition of cortical CCKergic neurotransmission in rats anticipating social defeat.