Behavioural Brain Research 321 (2017) 8–17 Contents lists available at ScienceDirect Behavioural Brain Research journal homepage: www.elsevier.com/locate/bbr Research report Adenosine A 2A receptor deletion affects social behaviors and anxiety in mice: Involvement of anterior cingulate cortex and amygdala Laura López-Cruz a , Maria Carbó-Gas a , Marta Pardo a , Pilar Bayarri a , Olga Valverde b , Catherine Ledent c , John D. Salamone d , Mercè Correa a,d,∗ a Àrea de Psicobiologia, Campus de Riu Sec, Universitat Jaume I, 12071 Castelló, Spain b Grup de Recerca en Neurobiologia del Comportament (GReNeC), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Hospital del Mar Medical Research Institute (IMIM), Dr. Aiguader 88, 08003 Barcelona, Spain c Universite Libre de Bruxelles, IRIBHM, Campus Erasme, CP602, route de Lennik 808, 1070 Bruxelles, Belgium d Department of Psychology, University of Connecticut, Storrs, CT, 06269-1020, USA h i g h l i g h t s • Blockade of adenosine A 2A receptors can potentiate motivation. • A 2A KO mice showed anxiety but are more socially oriented. • A 2A KO mice were less sensitive to social novelty. • c-Fos in A 2A KO mice was higher in anterior cingulate and amygdala than in WT mice. • A 2A receptors could be targets for pathologies such as autism and depression. a r t i c l e i n f o Article history: Received 27 July 2016 Received in revised form 10 December 2016 Accepted 16 December 2016 Available online 19 December 2016 Keywords: Social preference Social recognition Adenosine Aggressive behavior c-Fos Marble-burying test a b s t r a c t Blockade of adenosine A 2A receptors can potentiate motivation to work for natural reinforcers such as food. Conspecific interaction is a potent natural reinforcer in social animals that can be manifested as preference for social exploration versus other sources of novel stimulation. Deficiencies in this type of motivated behavior (social withdrawal) have been seen in several pathologies such as autism and depres- sion. However, the role of A 2A receptors in motivation for social interaction has not been widely explored. Social interaction paradigms evaluate the natural preference of animals for exploring other conspecifics, and the ability to differentiate between familiar versus novel ones. Anxiety is one of the factors that can induce avoidance of social interaction. In the present study, adenosine A 2A knockout (A 2A KO) and wild-type (WT) mice were assessed for social and anxiety-related behaviors. c-Fos immunoreactivity was evaluated as a measure of neuronal activation in brain areas involved in different aspects of moti- vation and emotional processes. Although A 2A KO mice showed an anxious profile, they displayed higher levels of sociability and were less sensitive to social novelty. WT mice displayed a typical pattern of social recognition 24 h later, but not A 2A KO mice, which explored equally both conspecifics. There were no differences between strains in aggressiveness, perseverance or social odor preferences. c-Fos immunore- activity in A 2A KO mice was higher in anterior cingulate and amygdala compared to WT mice. Thus, A 2A receptors appear to be potential targets for the improvement of pathologies related to social function. © 2016 Elsevier B.V. All rights reserved. 1. Introduction Adenosine is a central nervous system (CNS) neuromodulator that in the brain acts mainly via the activation of A 1 and A 2A ∗ Corresponding author at: Àrea de Psicobiologia, Campus de Riu Sec, Universitat Jaume I, 12071 Castelló, Spain. E-mail address: correa@psb.uji.es (M. Correa). G-protein coupled receptors [1]. While A 1 receptors are widely dis- tributed in the brain, A 2A receptors are predominantly localized and highly concentrated in the basal ganglia. Nucleus accum- bens and caudate/putamen have a high concentration of adenosine A 2A receptors [2–4], and considerable evidence indicates that A 2A receptors modulate the activational component of motivated behaviors (for a recent review see Ref. [5]). Administration of A 2A antagonists increases the selection of high-effort instrumen- http://dx.doi.org/10.1016/j.bbr.2016.12.020 0166-4328/© 2016 Elsevier B.V. All rights reserved.