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.
Blank
Thomas
T
Department of Molecular Neuroendocrinology, Max Planck Institute for Experimental Medicine, Hermann-Rein-Street 3, D-37075 Goettingen, Germany. blank@em.mpg.de
Nijholt
Ingrid
I
Vollstaedt
Stefanie
S
Spiess
Joachim
J
D000818:Animals; D001143:Arousal / Q000187:drug effects*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D003214:Conditioning, Classical / Q000187:drug effects*; D046508:Culture Techniques; D005239:Fear / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D007274:Injections, Intraperitoneal; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009473:Neuronal Plasticity / Q000187:drug effects; D010913:Pituitary-Adrenal System / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D013315:Stress, Psychological / Q000150:complications*; D000099052:CRF Receptor, Type 1
C101628:CP 154526; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D017871:Calcium-Calmodulin-Dependent Protein Kinases