Ca2+ release from inositol 1,4,5-trisphosphate-sensitive Ca2+ store by antidepressant drugs in cultured neurons of rat frontal cortex.
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 Ca(2+)-sensitive fluorescent indicator fura-2. Amitriptyline, imipramine, desipramine, and mianserin elicited transient increases in [Ca2+]i in a concentration-dependent manner (100 microM 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 microM), 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 microM) or acetylcholine (10 microM), 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.
Shimizu
M
M
Department of Psychiatry and Neuroscience, Kure National Hospital, Hiroshima, Japan.
Nishida
A
A
Hayakawa
H
H
Yamawaki
S
S
D000109:Acetylcholine / Q000494:pharmacology; D000639:Amitriptyline / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D003891:Desipramine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D005625:Frontal Lobe / Q000378:metabolism*; D007099:Imipramine / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D007700:Kinetics; D008803:Mianserin / Q000494:pharmacology; D009355:Neomycin / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D000928:Antidepressive Agents; D000639:Amitriptyline; D008803:Mianserin; D015544:Inositol 1,4,5-Trisphosphate; D009355:Neomycin; D000109:Acetylcholine; D007099:Imipramine; D002118:Calcium; D003891:Desipramine