The aim of the present study was to examine the effect of chronic tricyclic antidepressants (TCAs) treatment on the density of alpha-adrenoceptors in the rat brain. Density of alpha1- and alpha2-adrenoceptors was measured in cortex and hippocampus of rats treated with imipramine (IMI, 5mg/kg body weight), desipramine (DMI, 10mg/kg body weight), clomipramine (CMI, 10mg/kg body weight) and amitriptyline (AMI, 10mg/kg body weight), for 40 days, using [3H]prazosin and [3H]clonidine, respectively. The density of cortical alpha1-adrenoceptors was significantly decreased with IMI (46%), DMI (21%), CMI (50%) and AMI (67%) treatment, without altering the affinity of the receptor. The density of cortical alpha2-adrenoceptors was also significantly decreased with DMI (69%), CMI (81%) and AMI (80%) treatment, without affecting the affinity for [3H]clonidine. The density of hippocampal alpha1-adrenoceptors was significantly decreased only with AMI treatment (47%), without affecting the affinity for [3H]prazosin. However, no change in hippocampal alpha2-adrenoceptor density was observed with any of these TCAs. The results suggest that chronic antidepressant (AD) treatment downregulates the cortical, but not hippocampal, alpha1- and alpha2-adrenoceptors in rat brain. The region-specific downregulation of alpha1- and alpha2-adrenoceptors density, which occur after prolonged AD treatment, may underline the therapeutic mechanism of action.