Temporal association of elevated cholecystokininergic tone and adolescent trauma is critical for posttraumatic stress disorder-like behavior in adult mice

Adolescent trauma (AT) is a common risk factor for adult-onset posttraumatic stress disorder (PTSD). However, the vulnerability to AT among different individuals varies dramatically, indicating that other cofactors are important. Despite extensive studies, the identification of those cofactors has had little success. Here, we found that after subjected to traumatic stress at postnatal day 25 (P25), a stage that is comparable to the human adolescent period, inducible/reversible forebrain-specific cholecystokinin receptor-2 transgenic (IF-CCKR-2 tg) mice exhibited a significantly higher level of PTSD-like behavior at a later life (adult) stage compared with their wild-type littermates. Moreover, in these traumatized IF-CCKR-2 tg mice, both the glucocorticoid negative feedback inhibition and spatial learning and memory were impaired. Interestingly, if the CCKR-2 transgene was specifically suppressed during the time of AT exposure, these observations were largely diminished, indicating that a temporal association of the elevated CCKergic tone and AT is pathogenically critical. Treatment of traumatized IF-CCKR-2 tg mice with fluoxetine, a selective serotonin reuptake inhibitor, for a period of 4 wk significantly attenuated the PTSD-like behavior and the impaired glucocorticoid negative feedback inhibition, but not the memory deficit, implying that the memory deficit is an independent post-AT clinical entity and not a consequence of PTSD. Taken together, these results reveal a dynamic role of the CCKergic system in the development of post-AT psychopathologies and suggest that a timely antagonism of CCKR-2 activity during AT exposure is a potential preventive strategy for post-AT psychopathologies including PTSD and cognitive dysfunction.