The corticotropin-releasing factor receptor 1 antagonist CP-154,526 reverses stress-induced learning deficits in mice

The neuropeptide corticotropin-releasing factor (CRF) coordinates the endocrine responses to stress as a major physiological regulator of the hypothalamic-pituitary-adrenal axis. We assessed the effect of the non-peptidergic CRF receptor 1 antagonist CP-154,526 on stress-induced changes in context-dependent fear conditioning and hippocampal synaptic plasticity. The learning impairment of mice trained immediately after 1 h immobilization could be overcome by preinjection of CP-154,526 before exposure to immobilization. Exposure to acute stress reduced the amount of autophosphorylated Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) in the hippocampal CA1 area. When animals were pretreated with CP-154,526 before immobilization, the amount of hippocampal autophosphorylated CaMKII was elevated. Electrophysiological studies in the hippocampal CA1 region of stressed animals revealed no significant effects of the CP-154,526 pretreatment on long-term potentiation but a significant elevation of paired-pulse facilitation (PPF) was observed. The CP-154,526-induced enhancements in fear conditioning and PPF could be prevented by the selective CaMKII inhibitor KN-62. Our results demonstrated that learning impairment after acute stress was antagonized by CP-154,526 pretreatment.