- Depression is associated with significant morbidity, mortality, and expense (both personal and economic). Premature discontinuation of antidepressant medication involves a high risk of relapse, i.e., 30–50% of patients will relapse during the following 4 months. Fast onset and prevention of relapse to drug use by depressive patients are the major goals of the present research. Flinders Sensitive Line (FSL) rats are a novel experimental model for depression. FSL rats exhibit behavioral features characteristic of depression, such as cognitive (learning) difficulties, sleep disturbances, reduced activity, and reduced body weight. Long‐term, but not acute, treatment of the FSL rats with antidepressant drugs diminishes, and in some cases abrogates, their behavioral manifestations of depression. We found that the total norepinephrine, dopamine, and serotonin content of the mesolimbic areas of the FSL rats was three‐ to fivefold higher than those in normal rat counterparts. We also found that long‐term treatment of the FSL rats with antidepressant drugs resulted in a return to normal of these norepinephrine, dopamine, and serotonin levels, but did not affect the levels in normal, healthy rats. These rats, therefore, fulfill the diagnostic symptoms of major depression in humans, and show a high face‐, construct‐ and predictive‐ validity. Recently, we found that FSL rats, treated with clinically used antidepressants (desipramine, fluoxetine, paroxetine, and nefazodone), can be followed for behavior improvements up to 6 months after treatment, albeit with different results related to certain drugs. The onset of action of these drugs also differed between treatments. The results obtained elucidate the potential screen for new antidepressants to provide an earlier onset and long‐lasting action than conventional antidepressant treatments. The results also facilitate identification of the pharmacodynamic processes and neuronal circuits involved in response to drugs that effectively treat depressive disorders, both of which are critical to the development of improved psychiatric treatments and prevention strategies. Drug Dev. Res. 50:392–399, 2000. © 2000 Wiley‐Liss, Inc.