Brain Research Bulletin 71 (2007) 376–385 Mechanisms underlying the long-term behavioral effects of traumatic experience in rats: The role of serotonin/noradrenaline balance and NMDA receptors N. Sziray a , Cs. Leveleki a , G. Levay a , B. Mark ´ o a , L.G. H´ arsing Jr. a , ´ E. Mikics b , B. Barsy b , J. Haller b,∗ a EGIS Pharmaceuticals Plc., Division of Preclinical Research, Budapest, Hungary b Institute of Experimental Medicine, Budapest, Hungary Received 28 September 2006; accepted 10 October 2006 Available online 3 November 2006 Abstract Traumatic stressors induce long-lasting changes in behavior. It is believed that all three glutamatergic, serotonergic and noradrenergic neu- rotransmission play a role in the development of such behavioral changes, but their relative importance and relationship is poorly understood. We have shown previously that a single exposure of rats to electric shocks induces social avoidance for about 10 days. Here we assessed social avoidance 24h after shock exposure in rats with chemically lesioned serotonergic and noradrenergic neurons. The effects of the NMDA receptor blocker MK-801 were also studied. When the serotonin/noradrenaline balance was shifted towards serotonergic dominance via chemical lesions, the behavioral dysfunction was markedly attenuated. The disruption of serotonergic neurotransmission (that lead to noradrenergic dominance) significantly increased the behavioral deficit. Shock responding was not secondary to lesion-induced differences in social behavior. Noteworthy, the brain noradrenaline/serotonin ratio correlated negatively with shock-induced social avoidance, suggesting that the ratio rather than absolute levels are important in this respect. In line with this assumption, double lesions had minor effects on social avoidance, suggesting that these monoamin- ergic systems modulate, but do not mediate the behavioral deficit. The blockade of NMDA receptors abolished the development of stress-induced social avoidance both when applied before shocks and when applied before behavioral testing. We confirmed that the long-term behavioral effects of traumatic experience result from glutamatergic activation, the effects of which are mediated by NMDA receptors. The development of the behavioral deficit is modulated by the balance between serotonergic and noradrenergic neurotransmission, possibly via effects on shock-induced glutamatergic activation. © 2006 Elsevier Inc. All rights reserved. Keywords: DSP-4; 5,7-DHT; Chemical lesion; MK-801; Social interaction; Anxiety 1. Introduction Post-traumatic stress disorder is a difficult to treat, yet com- mon disorder, which is associated with significant morbid- ity, mortality and societal burden. The first-line choices for monotherapy are the selective serotonin reuptake inhibitors sug- gesting that the enhancement of serotonergic neurotransmission is protective in this disorder [32]. Recent evidence suggests that the inhibition of noradrenergic neurotransmission by adrenocep- ∗ Corresponding author at: Institute of Experimental Medicine, P.O. Box 67, 1450 Budapest, Hungary. Tel.: +36 12109406; fax: +36 12109951. E-mail address: haller@koki.hu (J. Haller). tor blockers (especially  1 and  blockers) may also be useful for mitigating post-traumatic stress disorder symptoms or perhaps even preventing the development of the disorder [13,44,45,54]. These data suggest that serotonergic and noradrenergic neuro- transmission play opposite roles in post-traumatic stress dis- order. Yet, the interactions between the two neurotransmitter systems are poorly understood. Behavioral dysfunctions induced by unpredictable and uncontrollable aversive events were suggested to resemble post-traumatic stress disorder symptoms and thus may model this disorder in the laboratory. Such behavioral dysfunctions include fear responses to contexts or cues associated earlier with aversive experiences (e.g. electric shocks) [16,22,29], and long-term increases in anxiety-like behavior induced by 0361-9230/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.brainresbull.2006.10.006