AIMS: Self-medication with alcohol while being treated with antidepressants is a common problem in patients with depression. Both alcohol consumption and antidepressant administration can induce changes in the cardiac autonomic responses as indicated by heart rate variability (HRV). In this study, we examined cardiac autonomic responses induced by acute heavy alcohol exposure after SSRIs (selective serotonin reuptake inhibitors) medications. MAIN METHODS: Rats were randomly divided into 3 groups, the alcohol administrated (Alc group), paroxetine administrated (SSRI group), and the SSRI+Alc group. Serum samples were collected to measure blood alcohol concentration (BAC). Physiological and cardiac autonomic responses including mean arterial pressure (MAP), heart rate (HR), and HRV were also compared among groups. KEY FINDINGS: The SSRI group exhibited higher values of HRV and HF (high frequency) than did the Alc and SSRI+Alc groups after alcohol administration. In contrast to the Alc group, the SSRI+Alc group had significantly lower MAP than Alc group, and higher HR, standard deviation of NN-intervals (SDNN), SDNN to MRR ratio (CVNN), square root of the mean squared differences of the successive NN-intervals (RMSSD) and HF values after alcohol administration. SIGNIFICANCE: Our results indicate that SSRIs increased sympathetic activity and alcohol reduced it in rats. The present study represents an attractive area for further research.