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Effects of Social Defeat Stress on Dopamine D2 Receptor Isoforms And Prabhu et al. Behav Brain Funct (2018) 14:16 https://doi.org/10.1186/s12993-018-0148-5 Behavioral and Brain Functions RESEARCH Open Access Efects of social defeat stress on dopamine D2 receptor isoforms and proteins involved in intracellular trafcking Vishwanath Vasudev Prabhu1,2, Thong Ba Nguyen1,2, Yin Cui4, Young‑Eun Oh1,2, Keon‑Hak Lee3, Tarique R. Bagalkot5 and Young‑Chul Chung1,2* Abstract Background: Chronic social defeat stress induces depression and anxiety-like behaviors in rodents and also responsi‑ ble for diferentiating defeated animals into stress susceptible and resilient groups. The present study investigated the efects of social defeat stress on a variety of behavioral parameters like social behavior, spatial learning and memory and anxiety like behaviors. Additionally, the levels of various dopaminergic markers, including the long and short form of the D2 receptor, and total and phosphorylated dopamine and cyclic adenosine 3′,5′-monophosphate regulated phosphoprotein-32, and proteins involved in intracellular trafcking were assessed in several key brain regions in young adult mice. Methods: Mouse model of chronic social defeat was established by resident-intruder paradigm, and to evaluate the efect of chronic social defeat, mice were subjected to behavioral tests like spontaneous locomotor activity, elevated plus maze (EPM), social interaction and Morris water maze tests. Results: Mice were divided into susceptible and unsusceptible groups after 10 days of social defeat stress. The sus‑ ceptible group exhibited greater decreases in time spent in the open and closed arms compared to the control group on the EPM. In the social interaction test, the susceptible group showed greater increases in submissive and neutral behaviors and greater decreases in social behaviors relative to baseline compared to the control group. Furthermore, increased expression of D2L, D2S, Rab4, and G protein-coupled receptor associated sorting protein-1 was observed in the amygdala of the susceptible group compared to the control group. Conclusion: These fndings suggest that social defeat stress induce anxiety-like and altered social interacting behav‑ iors, and changes in dopaminergic markers and intracellular trafcking-related proteins. Keywords: Dopamine receptor isoforms, Elevated plus maze, GASP-1, Rab4, Social behaviors, Social defeat stress Background and drug abuse [1, 2]. Tis paradigm may also be useful Social defeat is the result of a confrontation between male for identifying the environmental factors associated with animals and is an ethologically relevant experimental schizophrenia given that social defeat results in defcits paradigm that can be used to understand the physiologi- in prepulse inhibition [3], an enhanced mesocorticolim- cal and behavioral adaptations to repeated social stress. bic dopamine response [4, 5], increased phasic activity in Te social defeat stress paradigm has been widely used ventral tegmental area (VTA) dopaminergic neurons [6], as an animal model for depression, anxiety disorders, reductions in striatal dopamine transporter (DAT) bind- ing [7], and behavioral and neuronal cross-sensitization to amphetamine [8]. *Correspondence: [email protected] Social defeat stress also induces depression-like behav- 1 Department of Psychiatry, Chonbuk National University Medical School, iors, such as a reduced sucrose preference, decreased Jeonju 561‑756, South Korea Full list of author information is available at the end of the article social interaction and, and enhances anxiety-like © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat​iveco​mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat​iveco​mmons​.org/ publi​cdoma​in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Prabhu et al. Behav Brain Funct (2018) 14:16 Page 2 of 17 behaviors [9, 10], such as more time spent in a dark box intracellular trafcking in several brain regions of mice in the light/dark preference test [11] and an enhanced known to be afected in stress-related disorders such as and prolonged response in the acoustic startle test [12]. anxiety and depressive disorders [31], and schizophrenia For the present study, a particular focus was placed on [32]. changes in social behaviors, including dominant and sub- missive behaviors, and social avoidance because these Methods symptoms are relatively commonly observed in patients Animals with depressive disorder or schizophrenia. Several stud- Te social defeat procedure included male C57BL/6N ies have addressed this issue but most have used rats [13] mice and male CD1 (ICR) mice (Orient Company; rather than mice [6, 14]. Seongnam, South Korea) aged 6 and 15 weeks, respec- Two isoforms of the dopamine D2 receptor (D2R) tively, and weighing 18–22 and 40–44 g, respectively, have been identifed; a long form (D2L) and a short form at the time of arrival. Te C57BL/6N mice were group- (D2S; [15]). Te two isoforms are generated by alterna- housed while the CD1 mice were single-housed. Te tive splicing of the same gene but show diferential dis- social interaction test included CD1 mice (4 weeks old) tributions [16] and functions [17, 18]. In the postmortem with similar weights that were matched to the C57BL/6N brains of patients with schizophrenia, there are changes mice. All animals were housed in temperature-controlled in the mRNA levels of both D2S and D2L: increased rooms at 22 °C under a 12 h light/dark cycle with ad libi- expression of D2S in the dorsolateral prefrontal cortex tum food and water and were handled daily for 1 week to (DLPFC) [19] and mixed results on D2L in the DLPFC minimize stress during the behavioral experiments. and frontal cortex [19, 20]. However, to date, no stud- All the protocols in this experiment complied with the ies have investigated the efects of social defeat stress National Institutes of Health’s Guide for the Care and on D2L or D2S except for one study from our research Use of Laboratory Animals (NIH Pub. No. 85-23, revised group [21], which found increased expression of D2S 1996) [33]. Te entire project was reviewed and approved and D2L in the prefrontal cortex (PFC) of susceptible by the Institutional Animal Care and Use Committee mice compared to controls. Dopamine and cyclic adeno- (cuh-IACUC-151027-32) of Chonbuk National Univer- ′ ′ sine 3 ,5 -monophosphate-regulated phosphoprotein-32 sity Medical School on the basis of 3Rs (replacement, (DARPP-32) play central roles in mediating the efects refnement and reduction). of dopamine and glutamate [22, 23] and their expression can be altered by acute stress [24] and electroconvulsive Study design stimulation [25]. Our research group reported signifcant increases in the expression of total DARPP-32 and phos- Following the 1-week habituation period, the behav- phorylated DARPP-32 (p-DARPP-32) in the PFC and ioral tests were initiated in order of stress intensity amygdala (AMY) of defeated mice [26]. However, those (Fig. 1). Next, the C57BL/6N mice were subjected to the studies did not separate defeated mice into susceptible chronic social defeat procedure for 10 consecutive days; and unsusceptible groups, which is important for explor- the defeated mice were categorized into susceptible and ing the mechanisms that underlie the susceptibility to unsusceptible groups based on performance in the social stress. avoidance test. Ten, the behavioral tests were performed Schubert et al. [27] proposed that abnormalities in again. On day 39, the mice were sacrifced and brain tis- clathrin-mediated endocytosis and protein trafcking sues were obtained for the molecular studies. are core pathophysiological processes associated with schizophrenia and bipolar disorder. Of the various pro- Behavioral tests teins involved in the trafcking of dopamine receptors, All mice were habituated to the behavioral testing room three are of particular interest: ADP-ribosylation factor for 30–60 min prior to all behavioral tests. After each 6 (ARF-6; [28]), Rab proteins [29] and G protein-coupled behavioral test mice were rested for 1 day. receptor (GPCR) associated sorting protein-1 (GASP-1; [30]) because they are involved in the regulation of vesic- Spontaneous locomotor activity ular trafc and organelle structure and associated with Locomotor activity was measured in an open acrylic box the degradation of D2Rs respectively. (30 × 40 × 50 cm) using a video tracking system with Tus, the present study aimed to investigate the efects SMART software (Panlab; Barcelona, Spain). Te mice of chronic social defeat on a variety of behavioral param- were placed into the testing apparatus and their activi- eters, including the social interaction, EPM, and MWM ties, including distance traveled, locomotion time, and tests, and the levels of dopaminergic markers (D2L, D2S, time spent in a central zone (defned as 25% or 50% of the and total and p-DARPP-32) and proteins involved in total box area), were recorded for 30 min. Prabhu et al. Behav Brain Funct (2018) 14:16 Page 3 of 17 Fig. 1 Timeline of the experimental procedures Social interaction test raised 0.25 cm to minimize the chance of a mouse falling. Te social interaction apparatus consisted of a standard Each mouse was placed in the center facing an open arm polypropylene rectangular box (30 cm height × 40 cm and allowed to explore the apparatus for 5 min. Times width × 50 cm length) with an open top in which each spent in the open and closed arms and the numbers of C57BL/6N mouse was paired with an unfamiliar CD1 open and closed arm entries were calculated; arm entries mouse with a similar weight. First, the C57BL/6N mice were defned as entry of all four paws into an arm [34].
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