Stimulation of 5-HT2 receptors in mammals by agonists causes detrimental neurological, psychological, and circulatory effects. 5-HT2 antagonists block the elicited effects, but by themselves, they do not cause any apparent behavioral, neurological or subjective effects. However, 5-HT2 antagonists increase slow wave sleep and have a therapeutic action on impaired circulation, dysthymia, and negative symptoms in schizophrenia. Chronic treatment of rodents with various 5-HT2 antagonists was reported to cause an anomalous desensitization and 5-HT2 receptor down regulation. In this study we further investigated the 5-HT2 receptor regulation in vivo and in vitro by agonist and antagonist treatment. Treatment of rats with the 5-HT2 agonist, 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) (2.5 mg/kg s.c., every 8 h), rapidly caused desensitization of the head twitch response (-20% and -80% after 2 and 4 injections) and a decrease in the number of frontal cortical 5-HT2 receptors labeled with [3H]ketanserin (-24% and -41%, 24 h after 2 and 4 injections). The receptor resynthesis/degradation revealed half-times of 5 days initially to 3 days in the later drug-free period. Administration of the antagonist ketanserin (2.5 mg/kg, s.c., every 8 h) 15 min before the agonist, antagonized the acute behavioral effect but did not prevent the 5-HT2 receptor down regulation after 4 treatments. In contrast, ketanserin by itself, given 4 times, caused a reduction in the Bmax-value of [3H]ketanserin binding by 19% and given 10 times it caused a reduction in the Bmax-values by 28% and 31% of [3H]ketanserin and [3H]DOB binding in the frontal cortex. Hence 5-HT2 receptors labeled by an antagonist and an agonist ligand were similarly decreased. In vascular smooth muscle cells in culture kept for at least 24 h in a serotonin-free medium before treatment, the 5-HT2 receptor mediated 5-HT-induced inositol phosphate formation, was rapidly desensitized by agonist treatment: -20% after 15 min and -80% after 1 h incubation of the cells with 10(-5) M 5-HT or DOM. After 2 h and 24 h treatment resensitization occurred with half-times of 5 h and 12 h, respectively. Pretreatment of the cells for 15 min or 24 h with 10(-7) M of the antagonists setoperone or ketanserin, followed by extensive washing, caused a reduction in the 5-HT-induced inositol phosphate formation by about 50% with setoperone and by 30% with ketanserin. Effects of 15 min and 24 h drug pretreatment were similar.(ABSTRACT TRUNCATED AT 400 WORDS)