The neurokinin-3 receptor agonist senktide facilitates the integration of memories for object, place and temporal order into episodic memory Owen Y. Chao a , Susanne Nikolaus b , Joseph P. Huston a,⇑ , Maria A. de Souza Silva a a Center for Behavioral Neuroscience, Institute of Experimental Psychology, University of Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany b Clinic of Nuclear Medicine, University Hospital Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany article info Article history: Received 5 May 2014 Revised 5 June 2014 Accepted 16 June 2014 Available online 24 June 2014 Keywords: NK3 receptors Senktide Episodic-like memory Object recognition abstract Senktide, a potent neurokinin-3 receptor (NK3-R) agonist, has been shown to have promnestic effects in adult and aged rodents and to facilitate episodic-like memory (ELM) in mice when administrated before the learning trial. In the present study we assessed the effects of senktide on memory consolidation by administering it post-trial (after the learning trial) in adult rats. We applied an ELM test, based on the integrated memory for object, place and temporal order, which we developed (Kart-Teke, de Souza Silva, Huston, & Dere, 2006). This test involves two learning trials and one test trial. We examined inter- vals of 1 h and 23 h between the learning and test trials (experiment 1) in untreated animals and found that they exhibited intact ELM after a delay of 1 h, but not 23 h. In another test for ELM performed 7 days later, vehicle or senktide (0.2 mg/kg, s.c.) was applied immediately after the second learning trial and the test was conducted 23 h later (experiment 2). Senktide treatment recovered components of ELM (mem- ory for place and object) compared with vehicle-treated animals. After one more week, vehicle or senktide (0.2 mg/kg, s.c.) was applied post-trial and the test conducted 6 h later (experiment 3). The senk- tide-treated group exhibited intact ELM, unlike the vehicle-treated group. Finally, animals received post-trial treatment with either vehicle or SR142801, a selective NK3-R antagonist (6 mg/kg, i.p.), 1 min before senktide injection (0.2 mg/kg, s.c.) in the ELM paradigm and were tested 6 h later (experi- ment 4). The vehicle + senktide group showed intact ELM, while the SR142801 + senktide group did not. The results indicate that senktide facilitated the consolidation or the expression of ELM and that the senk- tide effect was NK3-R dependent. Ó 2014 Elsevier Inc. All rights reserved. 1. Introduction The neurokinin systems include the neuropeptides substance P (SP), neurokinin A (NKA) and neurokinin B (NKB), along with their corresponding G-protein-coupled neurokinin receptors (NK-R): the NK1-, NK2- and NK3-R (Massi, Panocka, & de Caro, 2000). The NK3-R are distributed throughout the mammalian brain including in areas strongly involved in ‘‘cognitive’’ functions, such as the prefrontal cortex, amygdala, medial septum, midbrain and hippocampus (Dam, Escher, & Quirion, 1990; Ding et al., 1996; Duarte, Schutz, & Zimmer, 2006; Langlois, Wintmolders, te Riele, Leysen, & Jurzak, 2001; Shughrue, Lane, & Merchenthaler, 1996). They are also widely expressed in neocortex, ventral tegmental area (VTA), substantia nigra (SN) and hypothalamus (Mileusnic et al., 1999). NK3-R have been strongly implicated in processes underlying learning and memory: NK3-R knockout mice were shown to be impaired in learning of conditioned avoidance and Morris water maze escape tasks (Siuciak et al., 2007). Systemic administration of senktide, a high affinity NK3-R agonist (Laufer, Gilon, Chorev, & Selinger, 1986; Massi et al., 2000), facilitated episodic-like mem- ory in adult mice (Zlomuzica, Dere, Huston, & de Souza Silva, 2008) and aged rats (Schäble et al., 2011). Senktide attenuated scopol- amine, a muscarinic acetylcholine (ACh)-R antagonist, -induced impairments of spatial working memory in a spontaneous alterna- tion task in mice (Kameyama, Ukai, & Shinkai, 1998; Ukai, Shinkai, & Kameyama, 1996; Ukai, Shinkai, & Kameyama, 1998) as well as scopolamine-induced deficits in recognition memory for object, place and temporal order in rats (Schäble, Huston, Barros, Tomaz, & de Souza Silva, 2012). Furthermore, cognitive performance of elderly humans was found to be correlated with the NK3-R-coding gene TACR3 (de Souza Silva et al., 2013). It is likely that NK3-R influence learning and memory via cholinergic modulation, since NK3-R are expressed on cholinergic http://dx.doi.org/10.1016/j.nlm.2014.06.009 1074-7427/Ó 2014 Elsevier Inc. All rights reserved. ⇑ Corresponding author. Fax: +49 211 81 12024. E-mail address: jph@uni-duesseldorf.de (J.P. Huston). Neurobiology of Learning and Memory 114 (2014) 178–185 Contents lists available at ScienceDirect Neurobiology of Learning and Memory journal homepage: www.elsevier.com/locate/ynlme