title: Wnt/β-catenin pathway in the prefrontal cortex is required for cocaine-induced neuroadaptations.
abstract: Behavioral sensitization is a progressive and enduring enhancement of the motor stimulant effects elicited by repeated administration of drugs of abuse. It can be divided into two distinct temporal and anatomical domains, termed initiation and expression, which are characterized by specific molecular and neurochemical changes. This study examines the role of the Wnt canonical pathway mediating the induction of cocaine sensitization. We found that β-catenin levels in the prefrontal cortex (PFC), amygdala (Amyg) and dorsal striatum (CPu) are decreased in animals that show sensitization. Accordingly, GSK3β activity levels are increased in the same areas. Moreover, β-catenin levels in nuclear fraction, mRNA expression of Axin2 and Wnt7b are decreased in the PFC of sensitized animals. Then, in order to demonstrate that changes in the PFC are crucial for initiation of sensitization, we either rescue β-catenin levels with a systemic treatment of a GSK3β inhibitor (Lithium Chloride) or inhibit Wnt/β-catenin pathway with an intracerebral infusion of Sulindac before each cocaine injection. As expected, rescuing β-catenin levels in the PFC as well as CPu and Amyg blocks cocaine-induced sensitization, while decreasing β-catenin levels exclusively in the PFC exacerbates it. Therefore, our results demonstrate a new role for the Wnt/β-catenin pathway as a required neuroadaptation in inducing behavioral sensitization.
authors.affiliation: Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina.|Douglas Mental Health University Institute, Canada.|Área Toxicología, Departamento de Ciencias de los Alimentos y del Medioambiente, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario (U.N.R), Argentina.
authors.forename: Santiago
authors.initials: S
authors.lastname: Cuesta
authors.affiliation: Área Toxicología, Departamento de Ciencias de los Alimentos y del Medioambiente, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario (U.N.R), Argentina.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Severin
authors.affiliation: Área Toxicología, Departamento de Ciencias de los Alimentos y del Medioambiente, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario (U.N.R), Argentina.
authors.forename: Jorgelina
authors.initials: J
authors.lastname: Batuecas
authors.affiliation: Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina.|Área Toxicología, Departamento de Ciencias de los Alimentos y del Medioambiente, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario (U.N.R), Argentina.
authors.forename: Silvana B
authors.initials: SB
authors.lastname: Rosso
authors.affiliation: Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina.|Área Toxicología, Departamento de Ciencias de los Alimentos y del Medioambiente, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario (U.N.R), Argentina.
authors.forename: Alejandra M
authors.initials: AM
authors.lastname: Pacchioni
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D003042:Cocaine / Q000378:metabolism / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D023421:Models, Animal; D017397:Prefrontal Cortex / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D060449:Wnt Signaling Pathway
chemical_list: D018765:Dopamine Uptake Inhibitors; D003042:Cocaine
keywords: Wnt canonical pathway; cocaine neuroadaptations; prefrontal cortex; sensitization