The NMDA receptor antagonist CPP blocks the effects of predator stress on pCREB in brain regions involved in fearful and anxious behavior.

A 5-min unprotected exposure to a cat produces long-lasting anxiogenic effects on behavior which are NMDA receptor-dependent. Since phosphorylation of CREB is regulated by NMDA receptors and pCREB-like-immunoreactivity (lir) is increased after predator stress, we examined the effects of CPP (3-(2-carboxypiperazin4-yl)propyl-l-phosphonic acid), a competitive NMDA receptor antagonist, on predator stress-induced changes in pCREB-lir in brain areas implicated in fearful and anxious behavior. Areas examined included the amygdala, periqueductal gray (PAG), bed nucleus of the stria terminalis (BNST), anterior cingulate cortex (ACC), and dorsal medial hypothalamus (DMH). CPP blocked the predator stress-induced increase in pCREB-lir in the right lateral PAG and in several amygdala nuclei. CPP also reversed the predator stress-induced suppression of pCREB-lir in the BNST. Importantly, at least in the amygdala and PAG, the pattern of pCREB-lir was hemisphere- and AP plane-dependent. Our results suggest that several amygdala nuclei, the PAG, and the BNST, where predator stress changes pCREB-lir in a NMDA receptor-dependent manner, are candidate areas of neuroplastic change contributing to lasting changes in anxiety-like behaviors.