Ellagic acid (EA) is a polyphenol that contributes to the nutraceutical properties of pomegranate. In the brain it was reported to control noradrenaline release. Recently, we demonstrated that EA binds α2 receptors (α2R), mimicking the full-agonist clonidine. The study was extended to Urolithins (URO) A, B and C which represent the main metabolites of EA in mammals, following a chronic (14 days) administration of an EA micro-formulation (EAm).“In vitro” studies were carried out on cortical and hippocampal synaptosomes isolated from control mice acutely exposed to the UROs, clonidine and yohimbine to assess their ability to modify the release of preloaded [3H]-noradrenaline ([3H]NA). We also isolated cortical and hippocampal synaptosomes from EAm-treated mice (receiving 50 mg/Kg of EA for 14 days) to verify the efficiency of the [3H]NA exocytosis and the impact of clonidine on this functional parameter. Moreover, Western blot analysis was carried out to quantify the α2Rs density in both cortical and hippocampal preparations.Our results suggest that UROA, but not UROB and UROC, mimicked clonidine at the α2R in a yohimbine-dependent fashion. The “in vivo” EAm chronic administration silenced the presynaptic α2R autoreceptors, since clonidine could not further modify the [3H]NA exocytosis, as observed in untreated mice. The α2R protein density was reduced in EAm treated CNS when compared to controls.We propose that UROA behaves as an α2R agonist and that the chronic EAm administration desensitizes the presynaptic α2R autoreceptors, favouring the noradrenaline diffusion in the brain.