Quantitative receptor autoradiography was used to determine the distribution patterns of 5-CT-sensitive and 5-CT-insensitive binding of [H-3]5-HT to high-affinity sites in human cortex, putamen, and globus pallidus. The binding of H-3-5-HT was limited to 5-HT1D sites (5-CT-sensitive) by co-incubating pindolol and mesulergine with [H-3]5-HT, and by using 10-mu-M 5-HT to determine non-specific binding. The difference in the levels of binding between tissues exposed to the 5-CT-containing incubation media and tissue exposed to [H-3]5-HT in the presence of 100 nM 5-CT was defined as 5-CT-insensitive binding (5-HT1E). The 5-HT1D receptor density in the frontal cortex was 189 fmol/mg, 226 fmol/mg was present in the globus pallidus, while the density in the putamen was only 28 fmol/mg. The 5-HT1E receptor density was 146 fmol/mg in frontal cortex, 224 fmol/mg in putamen and 140 fmol/mg in globus pallidus. The differential distribution patterns of the high-affinity, 5-CT-sensitive and 5-CT-insensitive [H-3]5-HT binding sites indicate that these sites are expressed independently in human brain tissues. These data are supportive of and consistent with previous pharmacological data that led to the division of 5-HT1D receptors into 5-HT1D and 5-HT1E receptors and do not support the division of 5-HT1D receptors into 5-CT-sensitive and 5-CT-insensitive states.