European Journal of Pharmacology 885 (2020) 173527 Available online 29 August 2020 0014-2999/© 2020 Elsevier B.V. All rights reserved. Full length article The potential rewarding and reinforcing effects of the substituted benzofurans 2-EAPB and 5-EAPB in rodents Leandro Val Sayson a , Raly James Perez Custodio a , Darlene Mae Ortiz a , Hyun Jun Lee a , Mikyung Kim b , Youngdo Jeong c , Yong Sup Lee c , Hee Jin Kim a, ** , Jae Hoon Cheong a, d, * a Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University, 815 Hwarang-ro, Nowon-gu, Seoul, 01795, Republic of Korea b Department of Chemistry & Life Science, Sahmyook University, 815 Hwarang-ro, Nowon-gu, Seoul, 01795, Republic of Korea c Medicinal Chemistry Laboratory, Department of Pharmacy & Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul, 02447, Republic of Korea d School of Pharmacy, Jeonbuk National University, 567 Baekje-daero, Deokjin-gu, Jeonju-si, Jeollabuk-do, 54896, Republic of Korea A R T I C L E INFO Keywords: 2-EAPB 5-EAPB Conditioned place preference Self-administration Locomotor sensitization Abuse potential ABSTRACT Accounts regarding the use of novel psychoactive substances continue to escalate annually. These include reports on substituted benzofurans (SBs), such as 1-(1-benzofuran-2-yl)-N-ethylpropan-2-amine (2-EAPB) and 1-(1- benzofuran-5-yl)-N-ethylpropan-2-amine (5-EAPB). Reports on the deaths and adverse consequences from the use of SBs warrant the investigation of their mechanism, possibly predicting the effects of similar compounds. Accordingly, we investigated the possible rewarding and reinforcing effects of 2-EAPB and 5-EAPB through conditioned place preference (CPP), self-administration, and locomotor sensitization tests. We also determined the possible infuence of 2-EAPB and 5-EAPB administration on dopamine- and plasticity-related proteins in the nucleus accumbens and ventral tegmental area. 2-EAPB and 5-EAPB induced CPP at different doses and were self- administered by rats. Only 5-EAPB induced locomotor sensitization in mice. 2-EAPB and 5-EAPB did not alter the expressions of dopamine D1 and D2 receptors in the nucleus accumbens, nor changed tyrosine hydroxylase and dopamine transporter expressions in the ventral tegmental area. Both 2-EAPB and 5-EAPB enhanced deltaFosB, but not transcription factor cyclic AMP-response-element binding protein and brain-derived neurotrophic factor in the nucleus accumbens. Hence, the potential rewarding and reinforcing effects on rodents induced by 2-EAPB and 5-EAPB may possibly be associated with alterations in other neurotransmitter systems (besides mesolimbic) and/or neuro-plastic modifcations. 1. Introduction Globally, novel psychoactive substances constantly emerge from clandestine markets in order to circumvent the regulations prohibiting their use and distribution (Beltgens, 2017; Johnson et al., 2013; Smith and Garlich, 2013). As a result, the number of cases for the identifcation of these substances by drug monitoring agencies increases annually (Addiction, 2014; Welter-Luedeke and Maurer, 2016; UNODC, 2014). A contributing problem is the constant introduction of modifcations to the structure of recognized illicit drugs (Kikura-Hanajiri et al., 2014; Weaver et al., 2015). This creates new compounds that may possibly be susceptible for recreational use; some of such compounds include substituted benzofurans (SBs) (Dolan et al., 2017; Eshleman et al., 2019). Considered as the third most prominent group of novel psycho- active substances that recently emerged in the past decade (Roque Bravo et al., 2019), these empathogens (heightens emotional state) were re- ported to function mainly on the serotonergic system (Eshleman et al., 2019), yet still generating downstream effects on dopaminergic proteins (Rickli et al., 2015). Their actions on these neurotransmitter networks enable addictive effects, as evidenced by previous studies (Adamowicz et al., 2014; Cha et al., 2016; Dawson et al., 2014; Fuwa et al., 2016), making several of these SBs illegal in some countries (Fuwa et al., 2016). Among these recent SBs are 1-(1-benzofuran-2-yl)-N-ethylpropan-2-- amine (2-EAPB) and 1-(1-benzofuran-5-yl)-N-ethylpropan-2-amine * Corresponding author. Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University, 815 Hwarang-ro, Nowon-gu, Seoul, 01795, Republic of Korea. ** Corresponding author. E-mail addresses: hjkim@syu.ac.kr (H.J. Kim), cheongjh@syu.ac.kr (J.H. Cheong). Contents lists available at ScienceDirect European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar https://doi.org/10.1016/j.ejphar.2020.173527 Received 31 March 2020; Received in revised form 25 August 2020; Accepted 28 August 2020