Urocortin, the CRF 2 receptor and effects of anxiolytic drugs

Abstract

Corticotropin-releasing factor (CRF) ts the major regulator of the HPA axis, and plays a key role in coordinatiig the mammalian stress.response. Recently, the existence of two distinct CRF receptor subtypes has been demonstrated CRF, and CRFs; the CRF: receptor also existing in multiple splice variants. Neuroanatomlc and pharmacologic data suggests that the novel ncuropeptide, urocortin, may be the endogenous CRF? hgand. While there is a considerable amount of data that supports a role for CRF in stress responses, depression and anxiety, and perhaps drug abuse, little is known about the role of urocortin and the CRFz receptor system m basic or stress ncumbiology We have previously demonstrated that chronic oral administration of the anviolytic benzodiazepine. alprazolam, to Sprague-Dawley rats decreases basal HPA axis activity, CRF mRNA espresslon in the central nucleus of the amygdala, and CRF, receptor mRNA and binding in the basolateral amygdala. Here we report that contrary to the downregulation of CRF and its CRF, receptor, chronic alprazolam treatment produced significant increases in urocottin mF3A cxpresion in the Edinger-Wcstphal nucleus and CWZreceptor binding m the lateral septum and vmtromedial hypothalamus (VMH). This increase in urocottin mRNA expression was still evident following both Ilumazcnd-precipitated and spontaneous alprazolam wlthdravval While available data suggests a role for urocortm and the CRF? receptor in the regulation of food and water balance, our data, as well as other recent studies demonstrating decreased CRFz, receptor mRNA express!on following maternal deptivatlon and mcreased immobility m a forced swim test following administration of CRI:: receptor antlscnse, Indicate that the urocortin-CRF2 receptor system may play a role m stress-coping behaviors. Additionally, it IS intrigumg to note that the CRF-CRF, and urocortin-CRFZ systems are mverscly modulated following chrome ansiolytic administration. A simdar antlparallel relationship between the CRF and CRF2 reqtor systems has been reported m an anxiety model In rats based on adverse early-life expmencc Supported hy NIH DA08705 and MH42088