Mechanisms underlying the long-term behavioral effects of traumatic experience in rats: the role of serotonin/noradrenaline balance and NMDA receptors.

Traumatic stressors induce long-lasting changes in behavior. It is believed that all three glutamatergic, serotonergic and noradrenergic neurotransmission 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 24 h 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 monoaminergic 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.

Pharmacological evaluation of the stress-induced social avoidance model of anxiety.

We have shown earlier that mild electric shocks induce a lasting social avoidance in male rats. Here we investigated whether shock-induced social avoidance can be developed into a laboratory model of stress-induced anxiety. The putative new model would assess sub-chronic, stress-induced anxiety (as opposed to tests based on natural fear) in a heterologous context (as opposed to classical fear conditioning). A single exposure to mild electric shocks induced a robust social avoidance that lasted more than 5 days. Low doses of chlordiazepoxide (0.5, 1 mg/kg), diazepam (0.5, 1, 5 mg/kg), buspirone (0.3, 1 mg/kg), and fluoxetine (1, 3, 5 mg/kg) abolished this effect, whereas the anxiogenic compound m-chlorophenylpiperazine (0.5-3 mg/kg) induced social avoidance in unshocked rats. These effects were produced at doses that did not affect locomotion in the open field. Haloperidol (0.05, 0.1, 1, 5 mg/kg) influenced social avoidance at sedative doses only. The sensitivity of the model to anxiolytic agents was compromised at high (sedating) doses. Taken conjointly, these data show that shock-induced social avoidance can be used to assess the anxiolytic potential of compounds. In addition to predictive validity, the model appears to show construct and face validity as well: stress is among the etiological factors of, whereas social avoidance simulates the social deficits seen in, a variety of anxiety disorders. The model may be used to study the effects of anxiolytics on sub-chronic states of stress-induced anxiety.