, Volume 232, Issue 16, pp 3019–3031 | Cite as

Role of CB2 receptors in social and aggressive behavior in male mice

  • Marta Rodríguez-AriasEmail author
  • Francisco Navarrete
  • M. Carmen Blanco-Gandia
  • M. Carmen Arenas
  • María A. Aguilar
  • Adrián Bartoll-Andrés
  • Olga Valverde
  • José Miñarro
  • Jorge Manzanares
Original Investigation



Male CB1KO mice exhibit stronger aggressive responses than wild-type mice.


This study was designed to examine the role of cannabinoid CB2r in social and aggressive behavior.


The social interaction test and resident–intruder paradigm were performed in mice lacking CB2r (CB2KO) and in wild-type (WT) littermates. The effects of the CB2r selective agonist JWH133 (1 and 2 mg/kg) on aggression were also evaluated in Oncins France 1 (OF1) mice. Gene expression analyses of monoamine oxidase-A (MAO-A), catechol-o-methyltransferase (COMT), 5-hydroxytryptamine transporter (5-HTT), and 5-HT1B receptor (5HT1Br) in the dorsal raphe nuclei (DR) and the amygdala (AMY) were carried out using real-time PCR.


Group-housed CB2KO mice exhibited higher levels of aggression in the social interaction test and displayed more aggression than resident WT mice. Isolation increased aggressive behavior in WT mice but did not affect CB2KO animals; however, the latter mice exhibited higher levels of social interaction with their WT counterparts. MAO-A and 5-HTT gene expression was significantly higher in grouped CB2KO mice. The expression of 5HT1Br, COMT, and MAO-A in the AMY was more pronounced in CB2KO mice than in WT counterparts. Acute administration of the CB2 agonist JWH133 significantly reduced the level of aggression in aggressive isolated OF1 mice, an effect that decreased after pretreatment with the CB2 receptor antagonist AM630.


Our results suggest that CB2r is implicated in social interaction and aggressive behavior and deserves further consideration as a potential new target for the management of aggression.


CB2KO mice Social encounters Resident–intruder paradigm Aggression OF1 mice JWH133 Gene expression 



This work was supported by the following research grants: Ministerio de Ciencia e Innovación (SAF2011-23420 awarded to Jorge Manzanares; SAF2010-15793 awarded to Olga Valverde); Ministerio de Economía y Competitividad, Dirección General de Investigación (PSI2011-24762 awarded to PI Jose Miñarro); Generalidad Valenciana, Consejería de Educación (PROMETEO/2009/072 awarded to PI Jose Miñarro); Generalitat de Catalunya (2009SGR684 awarded to Olga Valverde); Instituto de Salud “Carlos III” (FIS); Redes Telemáticas de Investigación Cooperativa en Salud (RETICS); Red de Trastornos Adictivos (RTA); fondos FEDER (RD06/0001/1004 and RD12/0028/0019 awarded to PI Jorge Manzanares, RD06/001/0016 and RD12/0028/0005 awarded to PI Jose Miñarro, and RD06/001/1001 and RD12/0028/0024 awarded to PI Olga Valverde).

Supplementary material

213_2015_3939_MOESM1_ESM.docx (176 kb)
ESM 1 (DOCX 176 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Marta Rodríguez-Arias
    • 1
    • 2
    Email author
  • Francisco Navarrete
    • 2
    • 3
  • M. Carmen Blanco-Gandia
    • 1
    • 2
  • M. Carmen Arenas
    • 1
    • 2
  • María A. Aguilar
    • 1
    • 2
  • Adrián Bartoll-Andrés
    • 3
  • Olga Valverde
    • 2
    • 4
  • José Miñarro
    • 1
    • 2
  • Jorge Manzanares
    • 2
    • 3
  1. 1.Unidad de Investigación Psicobiología de las Drogodependencias, Departamento de Psicobiología, Facultad de PsicologíaUniversitat de ValènciaValenciaSpain
  2. 2.Red Temática de Investigación Cooperativa en Salud (RETICS-Trastornos Adictivos)Instituto de Salud Carlos III, MICINN and FEDERMadridSpain
  3. 3.Instituto de NeurocienciasUniversidad Miguel Hernández-CSICSan Juan de AlicanteSpain
  4. 4.Neurobiology of Behavior Research Group (GReNeC), Department of Health and Experimental SciencesUniversity Pompeu Fabra, IMIM (Hospital del Mar), Barcelona Biomedical Research Park (PRBB)BarcelonaSpain

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