Premenstrual dysphoric disorder (PMDD) is characterized by a range of physical and affective symptoms including anxiety, irritability, anhedonia, social withdrawal and depression. We demonstrate robust and reproducible depression-like behavior during progesterone withdrawal (PWD) protocols with different methodological variables. Comparable immobility in the forced swim test was evident with different routes of administration (i.e. injections vs. implants), with and without exogenous estrogens in addition to progesterone, and in both single and multiple withdrawal paradigms. Furthermore, withdrawal from physiological doses of progesterone resulted in modest social withdrawal in the social preference test and anhedonia in the saccharin preference test without altering general activity levels or total liquid consumption. However, progesterone withdrawal did not alter serotonin levels in the cortex or hippocampus. Furthermore tryptophan depletion did not augment immobility during PWD. Neither fluoxetine nor duloxetine reduced depression-like behavior during PWD in the forced swim test. In contrast, the tricyclic antidepressant, amitriptyline, was effective in reducing the immobility in forced swim test. These data demonstrate that progesterone withdrawal is a reproducible model of PMDD in several critical behavioral domains. Furthermore, these data do not support alterations in serotonin levels in the etiology of hormonally induced depression.