Corticotropin-releasing factor-1 receptor involvement in behavioral neuroadaptation to ethanol: A urocortin^sub 1^-independent mechanism

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 neuropeptide, corticotropin-releasing factor (CRF), may be the keystone in drug-induced neuroadaptation. Corticosterone-activated glucocorticoid receptors (ORs) 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... receptors. We posited that CRF... signaling pathways are crucial for EtOH-induced sensitization. We demonstrate that mice lacking CRF... receptors do not show psychomotor sensitization to EtOH, a phenomenon that was also absent in CRF... receptor double-knockout mice. Deletion of CRF... receptors alone did not prevent sensitization. A blunted endocrine response to EtOH was found only in the genotypes showing no sensitization. The CRF... receptor antagonist CP-154,526 attenuated the acquisition and prevented the expression of EtOH-induced psychomotor sensitization. Because CRF... receptors are also activated by urocortin-1 (Ucn...), we tested Ucn... knockout mice for EtOH sensitization and found normal sensitization in this genotype. Finally, we show that the OR antagonist mifepristone does not block the expression of EtOH sensitization. CRF and CRF... receptors, therefore, are involved in the neurobiological adaptations that underlie the development and expression of psychomotor sensitization to EtOH. A CRF/CRF...-mediated mechanism involving the HPA axis is proposed for acquisition, whereas an extrahypothalamic CRF/CRF... participation is suggested for expression of sensitization to EtOH. (ProQuest: ... denotes formulae/symbols omitted.)