Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 26, Pages 9070-9075Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0710181105
Keywords
addiction; CP-154,526; HPA axis; knockout mice; psychomotor sensitization
Categories
Funding
- NIAAA NIH HHS [R01AA013738, P60AA010760, R01 AA013331, R01AA13331, R01 AA013738, P60 AA010760] Funding Source: Medline
- NIMH NIH HHS [R01MH65689, R01 MH065689] Funding Source: Medline
- PHS HHS [UO1016647] Funding Source: Medline
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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 (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, 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 ROH, a phenomenon that was also absent in CRF1 + 2 receptor double-knockout mice. Deletion of CRF2 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(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, 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.
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