Contents lists available at ScienceDirect Progress in Neuropsychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp Adolescent forced swim stress increases social anxiety-like behaviors and alters kappa opioid receptor function in the basolateral amygdala of male rats E.I. Varlinskaya, J.M. Johnson, K.R. Przybysz, T. Deak, M.R. Diaz ⁎ Department of Psychology, Center for Development and Behavioral Neuroscience, Developmental Exposure Alcohol Research Center, Binghamton University, Binghamton, NY 13902, United States ARTICLE INFO Keywords: Stress Kappa opioid receptor Adolescent Amygdala Development Ontogeny ABSTRACT Adolescence is a developmental period marked by robust neural alterations and heightened vulnerability to stress, a factor that is highly associated with increased risk for emotional processing deficits, such as anxiety. Stress-induced upregulation of the dynorphin/kappa opioid receptor (DYN/KOP) system is thought to, in part, underlie the negative affect associated with stress. The basolateral amygdala (BLA) is a key structure involved in anxiety, and neuromodulatory systems, such as the DYN/KOP system, can 1) regulate BLA neural activity in an age-dependent manner in stress-naïve animals and 2) underlie stress-induced anxiety in adults. However, the role of the DYN/KOP system in modulating stress-induced anxiety in adolescents is unknown. To test this, we examined the impact of an acute, 2-day forced swim stress (FSS – 10 min each day) on adolescent (~postnatal day (P) 35) and adult Sprague-Dawley rats (~P70), followed by behavioral, molecular and electrophysiological assessment 24 h following FSS. Adolescent males, but not adult males or females of either age, demonstrated social anxiety-like behavioral alterations indexed via significantly reduced social investigation and preference when tested 24 h following FSS. Conversely, adult males exhibited increased social preference. While there were no FSS-induced changes in expression of genes related to the DYN/KOP system in the BLA, these behavioral alterations were associated with alterations in BLA KOP function. Specifically, while GABA transmission in BLA pyramidal neurons from non-stressed adolescent males responded variably (potentiated, suppressed, or was unchanged) to the KOP agonist, U69593, U69593 significantly inhibited BLA GABA transmission in the majority of neurons from stressed adolescent males, consistent with the observed anxiogenic phenotype in stressed adolescent males. This is the first study to demonstrate stress-induced alterations in BLA KOP function that may contribute to stress-induced social anxiety in adolescent males. Importantly, these findings provide evidence for potential KOP-dependent mechanisms that may contribute to pathophysiological interactions with subsequent stress challenges. 1. Introduction Anxiety disorders are one of the most common and debilitating mental illnesses worldwide. In the US, the estimated lifetime prevalence of anxiety disorders rises dramatically from ~15% at age 6 to > 30% by 18 years of age (Merikangas et al., 2010), reaching an average of 35.1% in adults (ages 30–44) (Kessler et al., 2005). Although our under- standing of age-dependent behavioral changes is increasing, the neu- robiological mechanisms that influence age disparities in anxiety dis- orders are not well understood. Importantly, adolescence is a developmental period in which the developing brain is highly vulnerable to stress (Bekhbat et al., 2018; Doremus-Fitzwater et al., 2009; Hollenstein et al., 2012; McCormick and Green, 2013; Tottenham and Galvan, 2016), which is associated with increased risk for emo- tional processing deficits, such as anxiety (Barrocas and Hankin, 2011; Grant et al., 2003). Preclinical studies have also shown a clear re- lationship between stress and the development of anxiety in adoles- cents. Specifically, various rodent models have demonstrated that ex- posure to stress during adolescence increased both non-social anxiety, as measured on an elevated plus maze (Caruso et al., 2018; Cotella et al., 2019; Page and Coutellier, 2018; Zhang and Rosenkranz, 2012) or light/dark box (Lovelock and Deak, 2019), and social anxiety, https://doi.org/10.1016/j.pnpbp.2019.109812 Received 4 January 2019; Received in revised form 5 November 2019; Accepted 6 November 2019 ⁎ Corresponding author at: Department of Psychology, Binghamton University, PO Box 6000, State University of New York, Binghamton, NY 13902-6000, United States. E-mail address: mdiaz@binghamton.edu (M.R. Diaz). Progress in Neuropsychopharmacology & Biological Psychiatry 98 (2020) 109812 Available online 07 November 2019 0278-5846/ © 2019 Published by Elsevier Inc. T