Clonidine is a well established antihypertensive agent that is also used effectively to treat a variety of psychiatric disorders. Clonidine is a prototypic imidazoline compound that acts as an alpha(2)-adrenergic agonist but possesses nearly equivalent affinity for non-adrenergic imidazoline binding sites (I-sites). Receptor autoradiography of [(3)H]-clonidine binding presented herein compares densities of alpha(2)-adrenoceptors and I-sites (under a noradrenergic-mask) in Brodmann's area 47 of the left orbitofrontal cortex (OFC) and in six amygdaloid nuclei of subjects with major depression (n=12) vs. controls with no psychiatric history (n=11). Postmortem diagnoses were made from psychiatric interviews with next-of-kin. [(3)H]-Clonidine binding to alpha(2)-adrenoceptors in each of six OFC layers was lower, although not reaching statistical significance in any one layer by multivariate analysis, in depressives vs. control subjects. Binding to I-sites was conversely higher in depressives compared to control OFC layers, but did not reach statistical significance alone. However, the ratios of alpha(2)-adrenoceptor : I-sites in all six layers of OFC of depressed subjects were nearly half that of control subjects (P<0.008). In amygdalas from a different group of depressed patients there were no changes in alpha(2)-adrenoceptors or I-sites, or their ratios, compared with controls. The results support previous western blot data indicating a cortex-selective shift away from alpha(2)AR towards I-site preponderance in depressed patients.