TY - JOUR
T1 - Role of corticotropin-releasing factor and corticosterone in behavioral sensitization to ethanol
AU - Pastor, Raúl
AU - Reed, Cheryl
AU - Meyer, Paul J.
AU - McKinnon, Carrie
AU - Ryabinin, Andrey E.
AU - Phillips, Tamara J.
PY - 2012/5/1
Y1 - 2012/5/1
N2 - 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 (CRF 1) in ethanol (EtOH)-induced psychomotor sensitization. CRF 1 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/CRF 1 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/CRF 1 in the acquisition of sensitization to EtOH. Extra-hypothalamic CRF/CRF 1 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 CRF 1 in drug-induced neuroplasticity, dependence, and addictive behavior.
AB - 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 (CRF 1) in ethanol (EtOH)-induced psychomotor sensitization. CRF 1 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/CRF 1 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/CRF 1 in the acquisition of sensitization to EtOH. Extra-hypothalamic CRF/CRF 1 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 CRF 1 in drug-induced neuroplasticity, dependence, and addictive behavior.
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U2 - 10.1124/jpet.111.190595
DO - 10.1124/jpet.111.190595
M3 - Article
C2 - 22333290
AN - SCOPUS:84859940325
SN - 0022-3565
VL - 341
SP - 455
EP - 463
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 2
ER -