In an attempt to understand the basis of the changes in the mesolimbic dopamine system that occur in response to chronic treatment with the antidepressant drug, desipramine HCl (DMI), we monitored changes in extracellular dopamine in ventral tegmental area (VTA) and nucleus accumbens septi (NAS) using in vivo microdialysis in freely moving animals. Early in treatment at a time before changes in the responsiveness of the dopamine system are observed, basal levels of dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were found to be increased in the VTA of rats treated with 5.0 mg/kg DMI twice daily for 6 days compared to those of saline-treated animals. After 12 days of treatment, and in a second group of animals after 18 days of treatment, basal levels of dopamine, DOPAC, HVA and 5HIAA, and levels in response to challenge with 1.5 mg/kg d-amphetamine sulphate were measured in the NAS. No differences in these measures taken in NAS were found between DMI- and saline-pretreated animals after 12 days of treatment. In DMI-treated animals tested after 18 days, the dopamine response to amphetamine was elevated compared to that of saline-treated animals. Furthermore, although there were no differences in basal levels of dopamine, basal levels of DOPAC and HVA were increased in DMI-treated animals. These findings lend support to the view that the time-dependent sensitization of dopaminergic function brought about by the tricyclic antidepressants may share processes in common with the development of sensitization to the indirect dopamine receptor agonist, amphetamine.