N-METHYL-D-ASPARTATE RECEPTORS IN THE AMYGDALA ARE NECESSARY FOR THE ACQUISITION AND EXPRESSION OF CONDITIONED DEFEAT A. M. JASNOW, M. A. COOPER AND K. L. HUHMAN* Center for Behavioral Neuroscience, Department of Psychology, MSC 2A1155, 33 Gilmer Street, Unit 2, Georgia State University, Atlanta GA 30303-3082, USA Abstract—Here, we describe a biologically relevant model called conditioned defeat that is used to examine behavioral responses to social defeat in Syrian hamsters. In this model experimental animals that are normally aggressive experi- ence social defeat and consequently display high levels of submissive/defensive behavior even in response to non- threatening conspecifics. N-methyl-D-aspartate (NMDA) re- ceptors within the amygdala play an important role in condi- tioned fear; therefore, the purpose of this study was to ex- amine whether NMDA receptors within the amygdala are necessary for the acquisition and expression of conditioned defeat. Specifically, the present study examined whether bi- lateral infusions of the NMDA receptor antagonist DL-2-ami- no-5-phosphonopentanoic acid (AP5; 0.625, 1.25, 2.5, 5.0, 10.0 g) into the amygdala would block the acquisition of conditioned defeat. Subsequently, we examined whether bi- lateral infusions of AP5 (0.625, 1.25, 2.5, 5.0 g) into the amygdala prior to testing would block the expression of con- ditioned defeat. Infusions of AP5 into the amygdala immedi- ately before the initial social defeat significantly reduced submissive/defensive behavior when hamsters were tested the following day with a non-aggressive intruder. Similarly, infusions of AP5 into the amygdala immediately before expo- sure to a non-aggressive intruder significantly attenuated the display of submissive/defensive behavior. These data dem- onstrate that NMDA receptors are necessary for both the acquisition and expression of conditioned defeat. We believe that conditioned defeat is a unique and valuable animal model with which to investigate the neurobiology of fear- related changes in social behavior. © 2003 IBRO. Published by Elsevier Ltd. All rights reserved. Key words: fear, anxiety, social stress, emotion, agonistic behavior, submission. Social stress, primarily in the form of conflict between individuals, is one of the most pervasive forms of stress experienced by many animal species. Exposure to social stress often produces pronounced changes in physiology and behavior. Over the last several years, our laboratory has been examining the mechanisms underlying an abrupt and prolonged change in social behavior that is observed following single and repeated exposure to social defeat. We have been using an ecologically relevant model that has been previously established in Syrian hamsters, called conditioned defeat (Potegal et al., 1993). Male Syrian ham- sters are normally aggressive animals that readily defend home territories from intruding conspecifics. However, if these animals are placed in a situation in which they ex- perience a mild social defeat from a larger, more aggres- sive animal, they subsequently become highly submissive and are virtually unable to reverse their subordinate social status. Following this experience, defeated hamsters do not defend their home territory, even against smaller, non- aggressive animals that they would have previously at- tacked and defeated. Instead of attacking intruding ani- mals, defeated hamsters vigorously avoid social interac- tion and submit to intruders without provocation. We believe that conditioned defeat is a unique and valuable animal model with which to investigate the neurobiology of fear-responsive behavior. Conditioned defeat is not simply a transient change in behavior, but rather a prolonged response to social defeat. For instance, following four 5 min exposures to social defeat, male hamsters become submissive to non-aggres- sive intruders for a period that can last from at least 16 days to over 1 month without further experience of defeat (Huhman et al., 2003). Interestingly, there is a sex differ- ence in the response to social defeat in this species; females show a greatly attenuated response to defeat compared with males, and this difference may be due to actions of the steroid hormone, estrogen (Huhman et al., in preparation). Recently, we have begun to uncover some of the mechanisms underlying the striking change in social behavior observed in males in this model. The amygdala plays an important role in regulating both the acquisition and expression of conditioned defeat. Specifically, infusion of the GABA A agonist, muscimol, into the central nucleus of the amygdala, either before the initial experience of defeat or immediately before testing, greatly reduces the duration of submissive behavior displayed by defeated hamsters (Jasnow et al., 2000). These data are consistent with previous studies implicating the amygdala in fear and anxiety (Muller et al., 1997; Wilensky et al., 2000; Hitch- cock and Davis, 1986; Hitchcock et al., 1989) In addition, corticotropin-releasing hormone (CRH) is also involved in regulating conditioned defeat. Central infusion of a non- specific CRH antagonist into the lateral ventricle immedi- ately before testing also reduces the duration of submis- sive behavior displayed by defeated hamsters (Jasnow et *Corresponding author. Tel: +1-404-651-1636; fax: +1-404-651- 3929. E-mail address: khuhman@gsu.edu (K. L. Huhman). Abbreviations: AP5, DL-2-amino-5-phosphonopentanoic acid; ANOVA, analysis of variance; BNST, bed nucleus of the stria terminalis; CRH, corticotropin-releasing hormone; MGluR5, metabotropic glutamate receptor; NMDA, N-methyl-D-aspartate. Neuroscience 123 (2004) 625– 634 0306-4522/04$30.00+0.00 © 2003 IBRO. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.neuroscience.2003.10.015 625