The frontal cerebral cortex was used for most binding studies. Amitriptyline, imipramine, desipramine, nortriptyline, iprindole and fluoxitene competed at several neurotransmitter receptor binding sites,but their relative potencies did not correlate with their clinical potencies. In general, the greatest potencies occurred at histamine Hl receptors, labeled by 3H mepyramine, but they were also potent at muscarinic cholinergic receptors labeled by 3H quinuclidinylbenzilate. Their relative potencies at alpha-adrenergic receptors labeled by 3H dioxane (WB-4101) were similar to effects at muscarinic receptors and correlated with sedation and relief of psychomotor agitation. 2 Distinct populations of 5-HT receptors were labeled, with 3H 5-HT ( 5-HT-1) and 3H spiroperidol (5-HT-2) respectively, 3H LSD labeling both sites to the same extent. The antidepressants were much more potent at the 5-HT-2 receptors than at the 5-HT-1 receptors, effects on 3H LSD binding being intermediate. The drugs were less potent at dopamine (DA) receptors labeled by 3H spiroperidol in the corpus striatum, and at beta-adrenergic receptors labeled by 3H dihydroalprenolol (DHA) than at any other receptor binding sites. Haloperidol and chlorpromazine had considerable affinities for several receptors, resembling the more active antidepressants at alpha-adrenergic and 5-HT-2 sites, and the most potent drugs at DA receptors. Amitriptyline, imipramine, desipramine, iprindole and pargyline reduced 3H DHA binding to beta-adrenergic, and 3H spiroperidol binding to 5-HT-2 receptors, by 20 and 40%, respectively. Desipramine reduced 3H DHA binding by 29% and binding to 5-HT-2 receptors by 21%. Binding to beta-adrenergic and 5-HT receptors was unaffected by methysergide, chlorpromazine, haloperidol and fluoxitene. 3H 5-HT binding.to 5-HT-1 receptors decreased with imipramine and pargyline. 3H LSD binding was affected in a manner intermediate to effects on 3H spiroperidol and 3H 5-HT binding. Long-term drug treatment had no effect on muscarinic cholinergic or alpha-adrenergic receptors. Neuroleptics, but not antidepressants, increased binding to 3H spiroperidol DA receptors in the corpus striatum.