title: Effects of repeated social defeat on adolescent mice on cocaine-induced CPP and self-administration in adulthood: integrity of the blood-brain barrier.
abstract: Social stress in adulthood enhances cocaine self-administration, an effect that has been related with an increase in extracellular signal-regulated kinase and p38α mitogen-activated protein kinase phosphorylation. A detrimental effect of cocaine on blood-brain barrier (BBB) integrity has also been reported. This study evaluates the effects of repeated social defeat (RSD) during adolescence on the reinforcing and motivational effects of cocaine in adult mice and the changes induced by RSD on BBB permeability. Cocaine self-administration, conditioned place preference and quantitative analysis of claudin-5, laminin, collagen-IV and IgG immunoreactivity took place 3 weeks after RSD. Mice socially defeated during adolescence developed conditioned place preference and exhibited reinstated preference with a non-effective dose of cocaine (1 mg/kg). RSD mice needed significantly more sessions than control animals for the preference induced by 25 mg/kg of cocaine to be extinguished. However, acquisition of cocaine self-administration (0.5 mg/kg per injection) was delayed in the RSD group. Mice exposed to RSD displayed significant changes in BBB structure in adulthood, with a marked reduction in expression of the tight junction protein claudin-5 and an increase in basal laminin degradation (reflected by a decrease in laminin and collagen-IV expression) in the nucleus accumbens and hippocampus. The detrimental effect induced by cocaine (25 mg/kg) on collagen-IV expression in the hippocampus was more pronounced in RSD mice. In summary, our findings suggest that stress and cocaine can increase the long-term vulnerability of the brain to subsequent environmental insults as a consequence of a sustained disruption of the BBB.
authors.affiliation: Unidad de Investigación Psicobiología de las Drogodependencias, Departamento de Psicobiología, Facultad de Psicología, Universitat de València, Spain.|Red de Trastornos Adictivos del Instituto de Salud Carlos III, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Rodríguez-Arias
authors.affiliation: Unidad de Investigación Psicobiología de las Drogodependencias, Departamento de Psicobiología, Facultad de Psicología, Universitat de València, Spain.|Red de Trastornos Adictivos del Instituto de Salud Carlos III, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Montagud-Romero
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Instituto de Investigación Sanitaria Hospital, Spain.|Red de Trastornos Adictivos del Instituto de Salud Carlos III, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Rubio-Araiz
authors.affiliation: Unidad de Investigación Psicobiología de las Drogodependencias, Departamento de Psicobiología, Facultad de Psicología, Universitat de València, Spain.|Red de Trastornos Adictivos del Instituto de Salud Carlos III, Spain.
authors.forename: María A
authors.initials: MA
authors.lastname: Aguilar
authors.affiliation: Laboratory of Neuropharmacology, Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, Spain.|Red de Trastornos Adictivos del Instituto de Salud Carlos III, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Martín-García
authors.affiliation: Laboratory of Neuropharmacology, Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, Spain.|Red de Trastornos Adictivos del Instituto de Salud Carlos III, Spain.
authors.forename: Roberto
authors.initials: R
authors.lastname: Cabrera
authors.affiliation: Laboratory of Neuropharmacology, Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, Spain.|Red de Trastornos Adictivos del Instituto de Salud Carlos III, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Maldonado
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Instituto de Investigación Sanitaria Hospital, Spain.|Red de Trastornos Adictivos del Instituto de Salud Carlos III, Spain.
authors.forename: Francesca
authors.initials: F
authors.lastname: Porcu
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Instituto de Investigación Sanitaria Hospital, Spain.|Red de Trastornos Adictivos del Instituto de Salud Carlos III, Spain.
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Colado
authors.affiliation: Unidad de Investigación Psicobiología de las Drogodependencias, Departamento de Psicobiología, Facultad de Psicología, Universitat de València, Spain.|Red de Trastornos Adictivos del Instituto de Salud Carlos III, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Miñarro
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D003042:Cocaine / Q000378:metabolism / Q000494:pharmacology*; D003214:Conditioning, Classical / Q000187:drug effects*; D008297:Male; D051379:Mice; D023421:Models, Animal; D012646:Self Administration; D012919:Social Behavior; D013315:Stress, Psychological / Q000378:metabolism
chemical_list: D003042:Cocaine
keywords: Blood-brain barrier; cocaine; conditioned place preference; self-administration; social defeat