title: Role of corticotropin-releasing factor and corticosterone in behavioral sensitization to ethanol.
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.
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon, USA.
authors.forename: Raúl
authors.initials: R
authors.lastname: Pastor
authors.forename: Cheryl
authors.initials: C
authors.lastname: Reed
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Meyer
authors.forename: Carrie
authors.initials: C
authors.lastname: McKinnon
authors.forename: Andrey E
authors.initials: AE
authors.lastname: Ryabinin
authors.forename: Tamara J
authors.initials: TJ
authors.lastname: Phillips
mesh_terms: D000818:Animals; D016739:Behavior, Addictive / Q000235:genetics / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects*; D003345:Corticosterone / Q000378:metabolism*; D003346:Corticotropin-Releasing Hormone / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism; D011596:Psychomotor Disorders / Q000235:genetics / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D057897:Reflex, Righting / Q000187:drug effects / Q000235:genetics; D054832:Urocortins / Q000235:genetics / Q000378:metabolism; D000099052:CRF Receptor, Type 1
chemical_list: D018019:Receptors, Corticotropin-Releasing Hormone; C549377:Ucn1 protein, mouse; D054832:Urocortins; D000431:Ethanol; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone; D008797:Metyrapone