Corticotropin-releasing factor-1 receptor involvement in behavioral neuroadaptation to ethanol: A urocortin1-independent mechanism
Published online on June 30, 2008 Proc. Natl. Acad. Sci. USA, 10.1073A 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
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
1 participation is suggested for expression of sensitization to
EtOH.
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