The aim of the present study was to determine whether tramadol, which has a potential antidepressant efficacy, evokes, when administered repeatedly, changes similar to the alterations induced by conventional antidepressant drugs. Repeated administration of tramadol (20 mg/kg i.p. for 21 days) enhanced the D-amphetamine-induced locomotor hyperactivity and increased the density of alpha(1)-adrenoceptors in the rat brain cortex, as measured by saturation analysis of [H-3]prazosin binding. Autoradiographic analysis of [H-3]7-OH-DPAT ANF [H-3]raclopride binding revealed a significant up-regulation of dopamine D2 and D3 receptors in the rat nucleus accumbens upon repeated treatment with tramadol. All the above-mentioned effects induced by repeated administration of tramadol resemble the effects induced by conventional antidepressants. However, tramadol when administered repeatedly did not increase the levels of mRNA encoding for brain-derived neurotrophic factor (BDNF) and its receptor, TrkB. This is what differs tramadol from conventional antidepressants, since neurotrophic effects of these drugs have recently been postulated. (C) 2004 Elsevier B.V. All rights reserved.