Corticotropin-releasing Factor-1 Receptor Involvement In Behavioral Neuroadaptation To Ethanol: A Urocortin_1-independent Mechanism

摘要

A common expression of neuroadaptations induced by repeated exposure to addictive drugs is a persistent sensitized behavioral response to their stimulant properties. Neuroplasticity underlying drug-induced sensitization has been proposed to explain compulsive drug pursuit and consumption characteristic of addiction. The hypothalamic-pituitary-adrenal (HPA) axis-activating neuropep-tide, corticotropin-releasing factor (CRF), may be the keystone in drug-induced neuroadaptation. Cortkosterone-activated glucocor-ticoid receptors (GRs) mediate the development of sensitization to ethanol (EtOH), implicating the HPA axis in this process. EtOH-induced increases in corticosterone require CRF activation of CRF_1 receptors. We posited that CRF_1 signaling pathways are crucial for EtOH-induced sensitization. We demonstrate that mice lacking CRF_1 receptors do not show psychomotor sensitization to EtOH, a phenomenon that was also absent in CRF_(1+2) receptor double-knockout mice. Deletion of CRF_2 receptors alone did not prevent sensitization. A blunted endocrine response to EtOH was found only in the genotypes showing no sensitization. The CRF_1 receptor antagonist CP-154,526 attenuated the acquisition and prevented the expression of EtOH-induced psychomotor sensitization. Because CRF_1 receptors are also activated by urocortin-1 (Ucn_1), we tested Ucn_1 knockout mice for EtOH sensitization and found normal sensitization in this genotype. Finally, we show that the GR antagonist mifepristone does not block the expression of EtOH sensitization. CRF and CRF_1 receptors, therefore, are involved in the neurobiological adaptations that underlie the development and expression of psychomotor sensitization to EtOH. A CRF/CRF_1-mediated mechanism involving the HPA axis is proposed for acquisition, whereas an extrahypothalamic CRF/CRF, participation is suggested for expression of sensitization to EtOH.