We examined the chronic effects of desipramine and mianserin on increases of intracellular Ca2+ concentration ([Ca2+]¡) induced by noradrenaline (NA), acetylcholine (ACh), or high K+ in cultured neurons of rat frontal cortex, using fluoromicroscopic analysis with Ca2+-sensitive dye fura-2. NA- and ACh-induced [Ca2+]¡ increases were abolished in the presence of 1 µM prazosin and 1 µM atropine, respectively, and partially inhibited in the absence of extracellular Ca2+. When cultures were treated with 1 µM desipramine for 5 days, the dose-dependent curves of NA- and ACh-induced (0.01–100 µM) [Ca2+]i increases were similar to those of the control cultures. Neither NA- nor ACh-induced [Ca2+]i increases were affected by desipramine exposure, even at a concentration of 10 µM. Treatment with mianserin (0.1, 1, or 10 µM) for 5 days had no effect on either NA- or ACh-induced [Ca2+]i increases. Additionally, [Ca2+]i increases induced by high K+ (12.5–50 mM) were not affected following chronic 10 µM desipramine exposure for 5 days. Thus, chronic anti-depressant exposure does not modify the [Ca2+]i increases mediated by α1-adrenoceptors, muscarinic cholinergic receptors, or voltage-sensitive Ca2+ channels. Changes in Ca2+ mobilization may not be one of the mechanisms of an