Tranylcypromine (TCP) is a commercially available antidepressant drug, and recent literature reports suggest that high doses of this drug may be particularly effective in treating refractory depression. Down-regulation of 5-HT2 receptors in rat cortex is an effect produced after chronic administration of several antidepressants, and we have conducted a chronic study comparing low- and high-dose TCP in this regard. Male Sprague-Dawley rats were administered TCP (0.5 or 2.5 mg/kg/day) or vehicle (distilled water) via Alzet minipumps implanted subcutaneously in the dorsal thoracic area. Groups of rats were killed 4, 10 or 28 days after pump implantation and whole cortex was dissected out and utilized for preparation of a membrane fraction. Binding studies were performed with this fraction using 3H-ketanserin as the radioligand. Down-regulation (decrease in Bmax) of the 5-HT2 binding site was observed in high-dose animals after 10 and 28 days but not after 4 days. Low-dose TCP had no effect on 5-HT2 densities at any time interval. The affinity of 3H-ketanserin for the 5-HT2 site was not affected by either dose at any time interval. These results suggest that down-regulation of the 5-HT2 site may contribute to the efficacy of high-dose TCP in the treatment of refractory depression.