5-HT1A receptor density was measured in brain regions of rats treated with imipramine (5 mg/kg body wt), desipramine (10 mg/kg body wt), clomipramine (10 mg/kg body wt) and trazodone (10 mg/kg body wt) for 40 days, using [3H]8-OH-DPAT. It was observed that chronic exposure to antidepressants (ADs) results in significant downregulation of 5-HT1A receptors (30-80%) in cortex with all the drugs. Interestingly, in hippocampus, imipramine treatment increased the 5-HT1A receptor density (48%). With trazodone, however, there was a significant decrease in the density of 5-HT1A receptors in hippocampus (79%). The affinity of [3H]8-OH-DPAT was increased with imipramine treatment both in cortex and hippocampus. With trazodone treatment the affinity of [3H]8-OH-DPAT to 5-HT1A receptors was significantly decreased only in cortex. There was no change in the basal adenylyl cyclase (AC) activity after exposure to any of the drugs. However, the 5-HT sensitive AC activity was significantly increased in cortex with imipramine (72%), clomipramine (20%) and trazodone (50%) treatment, whereas in hippocampus only imipramine (50%) and trazodone (60%) treatment significantly increased AC activity. In conclusion, chronic treatment with ADs results in downregulation of cortical 5-HT1A receptors along with concomitant increase in 5-HT stimulated AC activity suggesting the involvement of cortical 5-HT1A receptor-mediated AC responses in the mechanism of action of ADs.