Acute immobilization stress increased serotonin and 5-hydroxyindoleacetic acid levels, the 5-hydroxyindoleacetic/serotonin ratio, and the number of [3H]ketanserin binding sites, representing serotonin-2 type receptors, in the rat frontal cortex. Peripheral administration of propranolol or central administration of 6-hydroxydopamine abolished the stress induced elevation of [3H]ketanserin binding sites. Treatment with 6-hydroxydopamine did not affect the increase in serotonin and 5-hydroxyindoleacetic acid levels, and enhanced the increase in the 5-hydroxyindoleacetic acid/serotonin ratio produced by stress. Conversely, chemical serotoninergic denervation with 5,7-dihydroxytryptamine had no influence on the stress-induced elevation of [3H]ketanserin binding sites, but abolished the serotonin and 5-hydroxyindoleacetic acid increase produced by stress. These results suggest that an intact serotoninergic system is not essential for serotonin-2 type receptor regulation during stress. Instead, the noradrenergic system, most probably through stimulation of beta-adrenoreceptors, may control the regulation of [3H]ketanserin binding sites in the rat frontal cortex during acute stress.