Since the literature data do not provide enough information on the effects of amphetamine on the prefrontal cortex and since many controversial findings were reported in various rat strains we decided to compare adenylyl cyclase activity in the prefrontal cortex in various rat strains and test the effects of chronic amphetamine treatment (for 14 days) on the activity of this enzyme. Basal adenylyl cyclase activity was lower in Wistar rats than in Sprague-Dawley and Lewis rat strains. Amphetamine treatment produced in Wistar rats a substantial decrease in basal adenylyl cyclase activity. In Sprague-Dawley rats, we observed the highest enzyme activity which was slightly reduced after amphetamine treatment. In Lewis rats which had basal activity close to the activity of Wistar rats, amphetamine produced an increase in enzyme activity. The total adenylyl cyclase activity, estimated in the presence of forskolin, was the lowest in Wistar rats. The highest stimulation was observed in Lewis rats. Amphetamine treatment caused a very significant inhibition of total adenylyl activity in Wistar rats and a smaller inhibition in Sprague-Dawley rats. However, in Lewis rats amphetamine treatment increased the dose-response curve of forskolin stimulation. These results show that Lewis rats, compared to the other two strains, develop not only quantitatively but also qualitatively different responses.