title: Post-sensitization treatment with rimonabant blocks the expression of cocaine-induced behavioral sensitization and c-Fos protein in mice.
abstract: CB1 receptor antagonists have been shown to prevent acute and long-term behavioral effects of cocaine. Here we evaluate the effectiveness of the CB1 receptor antagonist rimonabant to modify sensitized responses to cocaine. Mice were treated with saline or cocaine injections in a 15-day intermittent sensitization treatment and subsequently treated with either vehicle, 1 or 10mg/kg rimonabant in the drug-associated environment for 8 consecutive days. Animals were then challenged with saline and cocaine in the open-field apparatus on subsequent days to evaluate the expression of conditioned and sensitized effects to cocaine. c-Fos protein expression was evaluated in the nucleus accumbens (NAcc), ventral tegmental area (VTA), basolateral amygdala (BLA), medial prefrontal cortex (mPFC) and caudate-putamen (CPu) after the last (cocaine) challenge. Previous treatment with 10mg/kg rimonabant blocked the expression of conditioned hyperlocomotion and behavioral sensitization to cocaine, but not acute cocaine-induced hyperlocomotion. These behavioral effects were accompanied by significant changes in c-Fos expression in the brain reward system. Chronic cocaine sensitization blunted a subsequent acute cocaine-induced increase in c-Fos protein in the NAcc, effect that was reversed by previous treatment with rimonabant. Treatment with 10mg/kg rimonabant also attenuated the significant increase in c-Fos expression in the CPu, mPFC and BLA induced by previous chronic sensitization with cocaine. Our findings add to the evidence that drugs targeting CB1 receptors are good candidates for the treatment of cocaine abuse and provide further insights into the mechanisms underlying endocannabinoid signaling within the brain reward system in the context of cocaine abuse.
authors.affiliation: Department of Health Sciences, Universidade Estadual de Santa Cruz, Rod. Ilhéus/Itabuna, Km 16, 45662-0 Ilhéus, BA, Brazil. Electronic address: edumarinho@hotmail.com.
authors.forename: Eduardo A V
authors.initials: EAV
authors.lastname: Marinho
authors.affiliation: Department of Health Sciences, Universidade Estadual de Santa Cruz, Rod. Ilhéus/Itabuna, Km 16, 45662-0 Ilhéus, BA, Brazil.
authors.forename: Alexandre J
authors.initials: AJ
authors.lastname: Oliveira-Lima
authors.affiliation: Department of Physiology, Universidade Federal de São Paulo, R. Botucatu, 862, São Paulo, SP, Brazil.
authors.forename: Thais S
authors.initials: TS
authors.lastname: Yokoyama
authors.affiliation: Department of Physiology, Universidade Federal de São Paulo, R. Botucatu, 862, São Paulo, SP, Brazil.
authors.forename: Renan
authors.initials: R
authors.lastname: Santos-Baldaia
authors.affiliation: Department of Pharmacology, Universidade Federal de São Paulo, R. Botucatu, 862, São Paulo, SP, Brazil.
authors.forename: Luciana T C
authors.initials: LTC
authors.lastname: Ribeiro
authors.affiliation: Department of Pharmacology, Universidade Federal de São Paulo, R. Botucatu, 862, São Paulo, SP, Brazil.
authors.forename: Marilia A
authors.initials: MA
authors.lastname: Baldaia
authors.affiliation: Department of Physiology, Universidade Federal de São Paulo, R. Botucatu, 862, São Paulo, SP, Brazil.
authors.forename: Raphael Wuo
authors.initials: RW
authors.lastname: da Silva
authors.affiliation: Department of Physiology, Universidade Federal de São Paulo, R. Botucatu, 862, São Paulo, SP, Brazil.
authors.forename: Andre Willian
authors.initials: AW
authors.lastname: Hollais
authors.affiliation: Department of Pharmacology, Universidade Federal de São Paulo, R. Botucatu, 862, São Paulo, SP, Brazil.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Talhati
authors.affiliation: Department of Physiology, Universidade Federal de São Paulo, R. Botucatu, 862, São Paulo, SP, Brazil.
authors.forename: Beatriz Monteiro
authors.initials: BM
authors.lastname: Longo
authors.affiliation: Department of Psychobiology, Universidade Federal de São Paulo, R. Botucatu, 862, São Paulo, SP, Brazil. Electronic address: berro.lf@gmail.com.
authors.forename: Lais Fernanda
authors.initials: LF
authors.lastname: Berro
authors.affiliation: Department of Pharmacology, Universidade Federal de São Paulo, R. Botucatu, 862, São Paulo, SP, Brazil; Department of Psychobiology, Universidade Federal de São Paulo, R. Botucatu, 862, São Paulo, SP, Brazil.
authors.forename: Roberto
authors.initials: R
authors.lastname: Frussa-Filho
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D010880:Piperidines / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D000077285:Rimonabant
chemical_list: D063387:Cannabinoid Receptor Antagonists; D010880:Piperidines; D016760:Proto-Oncogene Proteins c-fos; D011720:Pyrazoles; D003042:Cocaine; D000077285:Rimonabant
keywords: Behavioral sensitization; C-Fos expression; Cannabinoid; Cocaine; Conditioning; Rimonabant