Unfavourable social environments play a relevant role in the onset and progression of depressive disorders. The present study aimed at establishing a rodent model of depression based on a negative social episode followed by prolonged social isolation in rats. Adult male, wild-type rats were implanted with radiotelemetry transmitters for ECG, body temperature (T) and physical activity (Act) recordings. Treated animals were exposed to a social defeat episode followed by 4-week isolation (SDI, n=22), while control counterparts (CTR, n=22) remained undisturbed with their female partners. During the isolation period, cardiac sympathovagal balance in the open-field test (day 9 and 23 post-defeat) and hypothalamic-pituitary-adrenocortical axis (HPAA) reactivity to dexamethasone suppression test (day 10 post-defeat) were assessed. Before and after defeat, hedonic behavior (% sucrose solution consumption) was measured and heart rate (HR), T, and Act sampled around-the-clock to assess their circadian rhythmicity. At sacrifice, the heart and adrenal glands were removed, weighed and processed for anatomy and tissue morphometry analyses. Overall body weight gain was significantly slowed down in SDI rats as compared to CTR counterparts. In addition, defeated animals did not show habituation of cardiac autonomic responsivity (tachycardia and vagal withdrawal) upon re-exposure to an open field test. HPAA function appeared to be altered in SDI rats as compared to CTR counterparts, as shown by significantly higher plasma corticosterone levels following dexamethasone injection and adrenal hypertrophy. SDIs also exhibited a significant decrement of sucrose solution consumption (anhedonia) 3 weeks after defeat, as well as a reduction in the amplitude of HR and Act daily rhythms, especially across the first week of isolation. Social defeat and isolation did not significantly affect cardiac left ventricle anatomy, whereas a moderate hypertrophy was observed in the right ventricle. In conclusion, social defeat and a prolonged period of isolation produced a set of physiological, behavioral and structural changes in rats, which resemble those observed in depressed and chronically stressed subjects.