1. The effects of chronic administration with milnacipran and desipramine on the noradrenergic alpha 2-autoreceptor sensitivity in the rat hypothalamus were compared. 2. Rats were administered, in their diet, milnacipran (50 mg/kg/day for 21 days, 24 h wash-out), desipramine (35 mg/kg/day for 21 days, 24 h wash out) or desipramine (14 mg/kg/day for 21 days, 41 h wash-out). Hypothalamic slices were incubated with [3H]noradrenaline, superfused and stimulated electrically. 3. Chronic administration with milnacipran did not modify basal or electrically induced release of [3H]noradrenaline, tissue incorporation of [3H]noradrenaline or the sensitivity of the alpha 2-autoreceptor assessed by the inhibition of the stimulation-evoked release of [3H]noradrenaline by the alpha 2-adrenoceptor agonist, guanabenz, in comparison to controls. After chronic desipramine (35 mg/kg), basal and evoked release of [3H]noradrenaline were increased, tissue incorporation of [3H]noradrenaline decreased and the inhibitory effect of guanabenz was diminished. At the lower dose (14 mg/kg), chronic desipramine increased only the evoked release of noradrenaline but did not modify the sensitivity of the alpha 2-autoreceptor. 4. Desipramine at 35 mg/kg remains in the tissue after 24 h wash out, causing a reduction of uptake and complicating the interpretation of the data.