Abstract
Neuroadaptations underlying sensitization to drugs of abuse seem to influence compulsive drug pursuit and relapse associated with addiction. Our previous data support a role for the corticotropin-releasing factor (CRF) type-1 receptor (CRF1) in ethanol (EtOH)-induced psychomotor sensitization. CRF1 is endogenously activated by CRF and urocortin-1. Because genetic deletion of urocortin-1 did not affect EtOH sensitization, we hypothesized that CRF is the important ligand underlying EtOH sensitization. To test this hypothesis, we used heterozygous and homozygous knockout (KO) mice, which lack one or both copies of the gene coding for CRF, and their respective wild-type controls. EtOH sensitization was normal in heterozygous, but absent in homozygous, CRF KO mice. Corticosterone (CORT) levels were drastically reduced only in CRF KO mice. Because CRF/CRF1 initiate EtOH-induced activation of the hypothalamic-pituitary-adrenal axis, we investigated CORT effects on EtOH sensitization. The CORT synthesis inhibitor metyrapone prevented the acquisition, but not the expression, of EtOH sensitization. Exogenous CORT administration sensitized the locomotor response to a subsequent EtOH challenge; we observed, however, that the exogenous CORT levels necessary to induce sensitization to EtOH were significantly higher than those produced by EtOH treatment. Therefore, participation of CORT seems to be necessary, but not sufficient, to explain the role of CRF/CRF1 in the acquisition of sensitization to EtOH. Extra-hypothalamic CRF/CRF1 mechanisms are suggested to be involved in the expression of EtOH sensitization. The present results are consistent with current theories proposing a key role for CRF and CRF1 in drug-induced neuroplasticity, dependence, and addictive behavior.
Footnotes
This work was supported by the Department of Veterans Affairs and the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism [Grants R01-AA13331, P60-AA010760, R01-AA013738, R24-AA020245, U01016647].
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↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
ABBREVIATIONS:
- EtOH
- ethanol
- ANOVA
- analysis of variance
- BEC
- blood ethanol concentration
- CORT
- corticosterone
- CRF
- corticotropin-releasing factor
- CRF1
- CRF type-1 receptor
- CRF2
- CRF type-2 receptor
- D2
- DBA/2J
- GR
- glucocorticoid receptor
- HT
- heterozygous
- HPA
- hypothalamic-pituitary-adrenal
- KO
- knockout
- LORR
- loss of righting reflex
- MR
- mineralocorticoid receptor
- WT
- wild type
- CP-154,526
- N-butyl-N-ethyl-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidin-4-amine
- CRA-1000
- 2-(N-(2-methylthio-4-isopropylphenyl)-N-ethylamino-4-(4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)-6-methylpyrimidine).
- Received November 28, 2011.
- Accepted February 13, 2012.
- U.S. Government work not protected by U.S. copyright
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