The aim of the present study was to examine the effect of chronic antidepressants treatment on the density of α₁-adrenoceptor (AR) subtypes in rat brain. Density of total α₁ and α(1A)- and α(1Β)-ARs was measured in cortex and cerebellum of rats treated with amitriptyline (AMI), desipramine (DMI) and fluoxetine (FLX), (10 mg/kg body wt), for 30 days, using [³H]prazosin in presence and absence of WB-4101. The density of cortical total α₁-ARs was significantly decreased with AMI (54%) and DMI (25%) treatment, without altering the affinity of the receptor. Fluoxetine did not alter the density of cortical α₁-ARs. The density of cortical α(1A)-ARs was also significantly decreased with AMI (85%) and DMI (50%) treatment, without affecting the affinity. The density of cerebellar total α₁-ARs was significantly decreased with AMI (37%), DMI (50%) and FLX (70%) treatment, without affecting the affinity for [³H]prazosin. The density of α(1A)-ARs was significantly decreased with AMI (67%), DMI (59%) and FLX (92%) treatment. α(1B)-AR density was decreased only with FLX (47%) and DMI (47%) treatment. Correspondingly the basal IP3 and NE (10 μM) stimulated IP3 levels were significantly decreased in AMI (47%), DMI (22%) and FLX (48%) treated rat cortex. The results suggest that chronic antidepressant (AD) treatment down-regulates the cortical and cerebellar total α₁-ARs in rat brain. However, α(1A) subtype is predominantly down-regulated by AMI and DMI, where as FLX affects cerebellar α(1A)-ARs. The region-specific and subtype specific down-regulation of α₁-ARs density, which occurs after prolonged AD treatment, may underline the therapeutic mechanism of action.