ORIGINAL INVESTIGATION Reduction of ethanol intake by corticotropin-releasing factor receptor-1 antagonist in “heavy-drinking” mice in a free-choice paradigm Diego Correia & Bruno Jacson Martynhak & Marcela Pereira & Isadora Pozzetti Siba & Andrea Frozino Ribeiro & Rosana Camarini & Roseli Boerngen-Lacerda Received: 13 April 2014 /Accepted: 25 February 2015 # Springer-Verlag Berlin Heidelberg 2015 Abstract Rationale We hypothesized that the corticotropin- releasing factor (CRF) system is hyperresponsive in an- imals with high ethanol intake, which exhibits a reduc- tion of ethanol intake when administered with a CRF 1 receptor antagonist. Methods Outbred Swiss mice were subjected to a long-term, three-bottle, free-choice paradigm (5 and 10 % [v/v] ethanol and water) that consisted of four phases: acquisition (AC; 10 weeks), withdrawal (W; 2 weeks), reexposure (RE; 2 weeks), and quinine-adulteration (AD; 2 weeks). Based on individual ethanol intake, the mice were classified into three groups: A group, preference for ethanol and persistently high consumption during AD phase; B group, preference for etha- nol and a reduction of ethanol intake in the AD phase; and C group; preference for water during all phases. A control group only had access to water. CRF 1 receptor messenger RNA (mRNA) levels in the amygdala and the effect of the CRF 1 receptor antagonist CP-154,526 on ethanol and water intake in the subgroups were studied. Results CRF 1 transcript levels were higher in the B group than in the control group. The highest dose of CP-154,526 reduced ethanol intake and preference, with no changes in water con- sumption, in the A group compared with vehicle. The B group exhibited a reduction of both ethanol and water intake, with no changes in preference. The C group exhibited no changes in response to the CRF 1 antagonist. Conclusions CRF 1 receptors appear to be involved in ethanol consumption in mice with high ethanol consumption, and CRF system-mediated neuroadaptations depend on drinking profiles. Keywords Addiction . Ethanol . CRF . CP-154,526 . Free-choice paradigm Introduction Alcohol addiction (i.e., alcoholism) has been hypothe- sized as a cycle composed of three stages interacting with each other: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. Impulsivity, driv- en by positive reinforcement, dominates the early stages of alcoholism and compulsivity, driven by negative re- inforcement, dominates during later stages. Compulsive alcohol use during later stages is mediated by a loss of reward system function and recruitment of brain stress systems (Koob and Le Moal 1997; 2001; Koob and Volkow 2010). These latter systems include corticotropin-releasing fac- tor (CRF), its two receptor subtypes CRF-R1 and CRF-R2, and norepinephrine in the extended amygdala (Koob 2008). D. Correia : B. J. Martynhak : M. Pereira : I. P. Siba : R. Boerngen-Lacerda (*) Departamento de Farmacologia, Jardim das Américas, Universidade Federal do Paraná, P.O. Box 19031, Curitiba, PR 81531-990, Brazil e-mail: boerngen@ufpr.br A. F. Ribeiro Programa de Pós-Graduação em Neurociências, Faculdade de Filosofia de Ciências Humanas, Universidade Federal de Minas Gerais, Minas Gerais, MG 31270-901, Brazil R. Camarini Departamento de Farmacologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP 05508-900, Brazil Psychopharmacology DOI 10.1007/s00213-015-3909-y