Dopamine receptor D5 deficiency results in a selective reduction of hippocampal NMDA receptor subunit NR2B expression and impaired memory Rodrigo Moraga-Amaro a , Hugo Gonz  alez b , Valentina Ugalde b , Juan Pablo Donoso-Ramos a , Daisy Quintana-Donoso a , Marcelo Lara c , Bernardo Morales c , Patricio Rojas c , Rodrigo Pacheco b, d, * , Jimmy Stehberg a, ** a Laboratorio de Neurobiología, Centro de Investigaciones Biomedicas, Universidad Andres Bello, 8370146, Santiago, Chile b Laboratorio de Neuroinmunología, Fundaci on Ciencia & Vida, ~ Nu~ noa, 7780272, Santiago, Chile c Laboratorio de Neurociencias, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, 9170022, Santiago, Chile d Laboratorio de Neuroinmunología, Departamento de Ciencias Biol ogicas, Facultad de Ciencias Biol ogicas, Universidad Andres Bello, 8370146, Santiago, Chile article info Article history: Received 28 August 2015 Received in revised form 30 November 2015 Accepted 17 December 2015 Available online 20 December 2015 Keywords: Dopamine receptor D5 Knockout mice Spatial memory N-methyl-D-aspartate receptors Synaptic plasticity Long-term potentiation abstract Pharmacological evidence associates type I dopamine receptors, including subtypes D1 and D5, with learning and memory. Analyses using genetic approaches have determined the relative contribution of dopamine receptor D1 (D1R) in cognitive tasks. However, the lack of drugs that can discriminate between D1R and D5R has made the pharmacological distinction between the two receptors difficult. Here, we aimed to determine the role of D5R in learning and memory. In this study we tested D5R knockout mice and wild-type littermates in a battery of behavioral tests, including memory, attention, locomotion, anxiety and motivational evaluations. Our results show that genetic deficiency of D5R significantly im- pairs performance in the Morris water maze paradigm, object location and object recognition memory, indicating a relevant role for D5R in spatial memory and recognition memory. Moreover, the lack of D5R resulted in decreased exploration and locomotion. In contrast, D5R deficiency had no impact on working memory, anxiety and depressive-like behavior, measured using the spontaneous alternation, open-field, tail suspension test, and forced swimming test. Electrophysiological analyses performed on hippocampal slices showed impairment in long-term-potentiation in mice lacking D5R. Further analyses at the mo- lecular level showed that genetic deficiency of D5R results in a strong and selective reduction in the expression of the NMDA receptor subunit NR2B in the hippocampus. These findings demonstrate the relevant contribution of D5R in memory and suggest a functional interaction of D5R with hippocampal glutamatergic pathways. © 2015 Elsevier Ltd. All rights reserved. 1. Introduction The Dopaminergic system plays key roles in many aspects of brain function, including movement coordination, reward, endo- crine regulation, cognition and emotion (Jaber et al., 1996; Jackson and Westlind-Danielsson, 1994; Sibley, 1999). The dopaminergic system is mainly investigated as a modulator of motivational be- haviors, addiction and reward (Berridge, 2007; Everitt and Robbins, 2005; Goodman, 2008; Kelley and Berridge, 2002; Schultz, 1998; Wise and Bozarth, 1987; Zhang et al., 2007). The importance of dopamine in relation to cognition is well documented, with an essential role in learning and memory (Bliss and Collingridge, 1993; Robbins, 2003). A role for the hippocampal dopaminergic system has been demonstrated in several learning paradigms, including passive avoidance (Bernabeu et al., 1997), win-shift positive rein- forcement learning (Packard and White, 1991) and spatial naviga- tion (Gasbarri et al., 1996), while the prefrontal dopaminergic * Corresponding author. Laboratorio de Neuroinmunología, Fundaci on Ciencia & Vida, Av. Za~ nartu 1482, ~ Nu~ noa, 7780272, Santiago, Chile. ** Corresponding author. Laboratorio de Neurobiología, Centro de Investigaciones Biom edicas, Universidad Andres Bello, Av. República 217, Santiago 8370146, Chile. E-mail addresses: rpacheco@cienciavida.org (R. Pacheco), jstehberg@unab.cl (J. Stehberg). Contents lists available at ScienceDirect Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm http://dx.doi.org/10.1016/j.neuropharm.2015.12.018 0028-3908/© 2015 Elsevier Ltd. All rights reserved. Neuropharmacology 103 (2016) 222e235