Shimizu M, Nishida A, Zensho H, Yamawaki S
Department of Psychiatry and Neuroscience, Kure National Hospital, Japan.
J Pharmacol Exp Ther. 1996 Dec;279(3):1551-8.
In rat frontal cortical astrocytes, 5-hydroxytryptamine (5-HT), 5-carboxamidotryptamine and 5-methoxytryptamine elicited a concentration-dependent increase of cyclic AMP accumulation, with EC50 values of 137 +/- 7 nM (5-HT), 10.4 +/- 3.9 nM (5-carboxamidotryptamine) and 57.8 +/- 13.6 nM (5-methoxytryptamine). Accumulation of cyclic AMP stimulated by 5-HT (10 microM) was inhibited by methiothepin (IC50 = 21 +/- 13 nM) but not by pindolol, SCH 23390, ICS 205-930 or GR 113808. These pharmacological effects on cyclic AMP formation in astrocytes are consistent with those observed in 5-HT7 receptor binding studies. Indeed, reverse transcription-polymerase chain reaction analysis revealed the presence of 5-HT7 mRNA in astrocytes. Chronic exposure of astrocytes to mianserin (0.05-4 microM) or amitriptyline (1-8 microM) for 3 days produced a concentration-dependent enhancement of 5-HT-stimulated cyclic AMP accumulation, with EC50 values of 0.47 +/- 0.04 microM (mianserin) and 2.5 +/- 0.3 microM (amitriptyline). The enhancement of cyclic AMP accumulation was time dependent, reaching maximal levels within 2 days. Mianserin exposure (2 microM, for 3 days) resulted in a comparable enhancement of cyclic AMP accumulation mediated by 5-carboxamidotryptamine and 5-methoxytryptamine, whereas this treatment had no effect on cyclic AMP production induced by G protein-specific stimulators and catalytic subunit-selective stimulators. The mianserin-induced enhancement of 5-HT-stimulated cyclic AMP accumulation was decreased by methiothepin (IC50 = 15 +/- 8 nM) and significantly attenuated by pretreatment with 5-HT7 receptor antisense oligonucleotides, suggesting that chronic mianserin exposure produces an increase in 5-HT7 receptor activity. Chronic exposure to maprotiline, setiptiline or clomipramine (5 microM, for 3 days) mimicked the effect of mianserin. The enhancement of 5-HT7 receptor activity after chronic antidepressant exposure may be a mechanism underlying the therapeutic effects.
在大鼠额叶皮质星形胶质细胞中，5-羟色胺（5-HT）、5-羧酰胺色胺和5-甲氧基色胺引起环磷酸腺苷（cAMP）积累呈浓度依赖性增加，其半数有效浓度（EC50）值分别为137±7 nM（5-HT）、10.4±3.9 nM（5-羧酰胺色胺）和57.8±13.6 nM（5-甲氧基色胺）。5-HT（10 μM）刺激的cAMP积累受到甲硫哒嗪抑制（IC50 = 21±13 nM），但不受吲哚洛尔、SCH 23390、ICS 205-930或GR 113808抑制。这些对星形胶质细胞中cAMP形成的药理作用与5-HT7受体结合研究中观察到的一致。事实上，逆转录-聚合酶链反应分析显示星形胶质细胞中存在5-HT7 mRNA。星形胶质细胞长期暴露于米安色林（0.05 - 4 μM）或阿米替林（1 - 8 μM）3天会导致5-HT刺激的cAMP积累呈浓度依赖性增强，其EC50值分别为0.47±0.04 μM（米安色林）和2.5±0.3 μM（阿米替林）。cAMP积累的增强呈时间依赖性，在2天内达到最高水平。米安色林暴露（2 μM，持续3天）导致5-羧酰胺色胺和5-甲氧基色胺介导的cAMP积累有类似增强，而该处理对G蛋白特异性刺激剂和催化亚基选择性刺激剂诱导的cAMP产生无影响。米安色林诱导的5-HT刺激的cAMP积累增强受到甲硫哒嗪抑制（IC50 = 15±8 nM），并被5-HT7受体反义寡核苷酸预处理显著减弱，这表明长期米安色林暴露会使5-HT7受体活性增加。长期暴露于马普替林、塞替普汀或氯米帕明（5 μM，持续3天）可模拟米安色林的作用。慢性抗抑郁药暴露后5-HT7受体活性增强可能是其治疗作用的潜在机制。
