Involvement of both the serotonergic and the endogenous opioid systems in the onset of depressive behavior has been suggested. Previously we showed that serotonin (5-hydroxytryptamine) facilitates beta-endorphin release in the nucleus accumbens (NAcc). Herein, the microdialysis method was used to assess in vivo the effects of serotonin on beta-endorphin release in a rat model of depressive behavior (the Flinders sensitive line, FSL), before and after antidepressant treatment. The basal extracellular level of beta-endorphin in the NAcc of FSL rats did not differ significantly from that in control rats. However, serotonin-induced beta-endorphin release was impaired in FSL rats. Chronic treatment (18 days) with desipramine or paroxetine did not significantly affect the extracellular levels of beta-endorphin in the NAcc of either the FSL or control rats. However, the chronic antidepressant treatment did normalize the serotonin-induced release of beta-endorphin in FSL rats, as well as their behavioral manifestation of depressive behavior. Our results show that depressive behavior may relate to an impaired effect of serotonin on beta-endorphin release in the NAcc in a rat model of depression, and suggest a possible new mode of action of antidepressant drugs.