Abstract The aim of this study was to investigate the effect of citalopram, a selective serotonin reuptake inhibitor, on the sensitivity of rat vas deferens α2-adrenoceptors and to compare it with the effects of serotonin and the dual noradrenaline-serotonin uptake inhibitor duloxetine. To this end, we studied the inhibitory effect of the α2-adrenoceptor agonist bromoxidine on the electrically induced contraction of the vas deferens. Citalopram (1, 3 times 103 and 3 times 104 nm) applied in-vitro significantly attenuated the concentration-response inhibition induced by activation of α2-adrenoceptors on the electrically evoked contraction of the vas deferens (concentration of the agonist required to promote 50% of the maximal effect, EC50, for bromoxidine increased by 232%, 421% and 818%, respectively). Similarly, serotonin also attenuated the concentration-response inhibition mediated by presynaptic α2-adrenoceptors (96% increase in EC50). Acute and long-term systemic administration of citalopram and duloxetine also produced a loss in the sensitivity of α2-adrenoceptors to bromoxidine (EC50 for bromoxidine increased by 97% and 144%, respectively, after citalopram, and by 214% and 167% after duloxetine). In addition, we observed that an increased fraction of receptors was required to be occupied to yield 50% of the inhibitory effect of bromoxidine after long-term administration of citalopram and duloxetine (KE increased by 142% and 83%). These results are indicative of early-onset and persistent down-regulation of peripheral α2-adrenoceptors by citalopram, which may account for some of its side effects.