, Volume 236, Issue 9, pp 2797–2810 | Cite as

Pharmacological modulation of the behavioral effects of social defeat in memory and learning in male mice

  • M Carmen Blanco-Gandia
  • Sandra Montagud-Romero
  • Javier Navarro-Zaragoza
  • Elena Martínez-Laorden
  • Pilar Almela
  • Cristina Nuñez
  • Maria-Victoria Milanés
  • María-Luisa Laorden
  • José Miñarro
  • Marta Rodríguez-AriasEmail author
Original Investigation



Previous studies have demonstrated that repeated social defeat (RSD) stress only induces cognitive deficits when experienced during adulthood. However, RSD increases cocaine-rewarding effects in adult and adolescent mice, inducing different expressions of proBDNF in the ventral tegmental area.


The aim of the present study was to evaluate the effect of cocaine administration in socially defeated adult or adolescent mice on learning, memory, and anxiety. Additionally, the role of BDNF was also studied.


Adolescent and young adult mice were exposed to four episodes of social defeat or exploration (control), being treated with a daily injection of four doses of saline or 1 mg/kg of cocaine 3 weeks after the last social defeat. Other groups were treated with the TrkB receptor antagonist ANA-12 during this 21-day period. After this treatment, their cognitive and anxiogenic profiles were evaluated, along with the expression of BDNF, pCREB, and pERK1/2 in the dentate gyrus (DG) and basolateral amygdala (BLA).


Cocaine induced an increased expression of pCREB and BDNF in the DG and BLA only in defeated animals. Although RSD did not affect memory, the administration of cocaine induced memory impairments only in defeated animals. Defeated adult mice needed more time to complete the mazes, and this effect was counteracted by cocaine administration. RSD induced anxiogenic effects only when experienced during adulthood and cocaine induced a general anxiolytic effect. Blockade of Trkb decreased memory retention without affecting spatial learning and modified anxiety on non-stressed mice depending on their age.


Our results demonstrate that the long-lasting effects of social defeat on anxiety and cognition are modulated by cocaine administration. Our results highlight that the BDNF signaling pathway could be a target to counteract the effects of cocaine on socially stressed subjects.


Social defeat stress Adolescence Cocaine Anxiety Learning Memory BDNF ANA-12 



We wish to thank Guillermo Chuliá for his English language editing.

Funding information

Ministerio de Economía y Competitividad (MINECO), Dirección General de Investigación, PSI2014-51847-R and PSI 2017-83023-R; Ministerio de Ciencia e Innovación (SAF/FEDER 2013–49076-P), Spain; Instituto de Salud Carlos III, Red de Trastornos Adictivos (RTA) (RETICS RD06/0001/1006 and RD12/0028/0005) and Unión Europea, Fondos FEDER “A way to build Europe”; and Instituto Murciano de Investigación en Biomedicina (IMIB), Región de Murcia, Spain.

Compliance with ethical standards

All procedures were conducted in compliance with the guidelines of the European Council Directive 2010/63/UE regulating animal research and were approved by the local ethics committees (University of Valencia).

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

213_2019_5256_MOESM1_ESM.pptx (1 mb)
ESM 1 (PPTX 1042 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • M Carmen Blanco-Gandia
    • 1
  • Sandra Montagud-Romero
    • 2
  • Javier Navarro-Zaragoza
    • 3
  • Elena Martínez-Laorden
    • 3
  • Pilar Almela
    • 3
  • Cristina Nuñez
    • 3
  • Maria-Victoria Milanés
    • 2
    • 3
  • María-Luisa Laorden
    • 2
    • 3
  • José Miñarro
    • 1
    • 2
  • Marta Rodríguez-Arias
    • 1
    • 2
    Email author
  1. 1.Department of Psychobiology, Facultad de PsicologíaUniversitat de ValenciaValenciaSpain
  2. 2.Red Temática de Investigación Cooperativa en Salud (RETICS-Trastornos Adictivos)Instituto de Salud Carlos III, MICINN and FEDERMadridSpain
  3. 3.Murcia Research Institute of Health Sciences (IMIB) and Faculty of MedicineUniversity of MurciaMurciaSpain

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