- Rationale: Current hypotheses on the etiology of depression attribute the disorder to alterations in serotonin and norepinephrine neurotransmission. However, the relationship between these alterations and depressive behavior is poorly understood. Conversely, an interaction between the serotonergic and dopaminergic systems in the nucleus accumbens has been established. Since motivation and hedonia have been associated with dopamine release in the nucleus accumbens, we decided to test its modulation by serotonin in relation to depressive-like behavior. Objectives and methods: The extracellular dopamine levels in the nucleus accumbens were studied in vivo in Flinders Sensitive Line (FSL, a rat model of depressive behavior) and control rats, before and after antidepressant treatment. Rats were chronically treated with the antidepressants desipramine (5mg/kg/day) and paroxetine (7.5mg/kg/day) for 18 consecutive days. As a measure of depressive behavior we used a modified swim test. The release of dopamine in response to local serotonin application was monitored using the microdialysis technique. Results: Serotonin (0.5µM) facilitated dopamine release in the nucleus accumbens of control rats. In FSL rats, basal extracellular dopamine levels in the nucleus accumbens were 40% lower than in control rats and did not increase in response to serotonin stimulation. However, chronic antidepressant treatment of the FSL rats normalized the serotonin–dopamine interaction as well as their behavioral deficiencies. Conclusions: The inability of serotonin to stimulate dopamine release in the nucleus accumbens, thereby leading to anhedonia and lack of motivation, may therefore be an essential factor in the onset of depression and a target for modulation by antidepressant drugs.