Ca2+ Release from Inositol 1,4,5‐Trisphosphate‐Sensitive Ca2+ Store by Antidepressant Drugs in Cultured Neurons of Rat Frontal Cortex

Abstract

Abstract: The ability of antidepressant drugs (ADs) to increase the concentration of intracellular Ca2+ ([Ca2+]i) was examined in primary cultured neurons from rat frontal cortices using the Ca2+‐sensitive fluorescent indicator fura‐2. Amitriptyline, imipramine, desipramine, and mianserin elicited transient increases in [Ca2+]i in a concentration‐dependent manner (100 μM to 1 mM). These four AD‐induced [Ca2+]i increases were not altered by the absence of external Ca2+ or by the presence of La3+ (30 μM), suggesting that these ADs provoked intracellular Ca2+ mobilization rather than Ca2+ influx. All four ADs increased inositol 1,4,5‐trisphosphate (IP3) contents by 20–60% in the cultured cells. The potency of the IP3 production by these ADs closely correlated with the AD‐induced [Ca2+]i responses. Pretreatment with neomycin, an inhibitor of IP3 generation, significantly inhibited amitriptyline‐ and imipramine‐induced [Ca2+]i increases. In addition, by initially perfusing with bradykinin (10 μM) or acetylcholine (10 μM), which can stimulate the IP3 generation and mobilize the intracellular Ca2+, the amitriptyline responses were decreased by 76% and 69%, respectively. The amitriptyline‐induced [Ca2+]i increases were unaffected by treatment with pertussis toxin. We conclude that high concentrations of amitriptyline and three other ADs mobilize Ca2+ from IP3‐sensitive Ca2+ stores and that the responses are pertussis toxin‐insensitive. However, it seems unlikely that the effects requiring high concentrations of ADs are related to the therapeutic action. Copyright © 1993, Wiley Blackwell. All rights reserved