Odagaki Y
Department of Psychiatry and Neurology, Hokkaido University School of Medicine, Sapporo, Japan.
Hokkaido Igaku Zasshi. 1992 Mar;67(2):247-58.
The mechanisms of action of lithium and antidepressants were investigated with reference to effects of these drugs on monoaminergic receptors and receptor-coupled adenylate cyclase systems in rat brain. Oral administration of lithium carbonate for 21 days decreased significantly the density of beta-adrenergic receptors in rat cerebral cortex, which is the same change as reported as the result of long-term treatment with many antidepressants. With regard to 5-hydroxytryptamine (5-HT) receptor subtypes, lithium treatment reduced the maximum number of 5-HT1A receptors in rat hippocampus but not in cerebral cortex, whereas repetitive injections with imipramine or desipramine did not. beta-Adrenoceptor-coupled adenylate cyclase activity was subsensitized by long-term lithium treatment in consistency with above-mentioned down-regulation of beta-adrenergic receptors. Stimulation of adenylate cyclase activity by non-hydrolyzable GTP analogue, guanyl-5'-ylimidodiphosphate (Gpp(NH)p), was, however, unaltered in lithium-treated rats as compared with controls. On the other hand, 5-HT1A-mediated inhibition of forskolin-stimulated adenylate cyclase in rat hippocampal membranes was not altered by chronic treatment with lithium or antidepressants. Gpp(NH)p-induced inhibition of forskolin-stimulated adenylate cyclase activity was not influenced by lithium treatment, either. [3H]Forskolin binding to rat cerebral cortex, which is assumed to be associated with the activated complex of catalytic subunit of adenylate cyclase and stimulatory guanine nucleotide-binding regulatory proteins (Gs), was not changed by administration of lithium or antidepressants under any condition studied. Pertussis toxin (islet-activating protein, IAP) sensitive G proteins (Gi/Go) as determined by using IAP-catalyzed [32P]ADP-ribosylation was not altered by lithium- or antidepressant-treatment, either. The implication of these results is discussed with a view of clarifying the mechanisms of action of these thymoleptic drugs.
参照锂盐和抗抑郁药对大鼠脑内单胺能受体及受体偶联腺苷酸环化酶系统的影响，对它们的作用机制进行了研究。口服碳酸锂21天可显著降低大鼠大脑皮质中β - 肾上腺素能受体的密度，这与许多抗抑郁药长期治疗的结果所报道的变化相同。关于5 - 羟色胺（5 - HT）受体亚型，锂盐治疗可降低大鼠海马体中5 - HT1A受体的最大数量，但对大脑皮质无此作用，而反复注射丙咪嗪或去甲丙咪嗪则无此效果。长期锂盐治疗使β - 肾上腺素能受体偶联的腺苷酸环化酶活性发生脱敏，这与上述β - 肾上腺素能受体的下调一致。然而，与对照组相比，用不可水解的GTP类似物鸟苷 - 5'- 亚氨二磷酸（Gpp(NH)p）刺激锂盐处理大鼠的腺苷酸环化酶活性未发生改变。另一方面，锂盐或抗抑郁药的长期治疗并未改变大鼠海马体膜中5 - HT1A介导的对福斯高林刺激的腺苷酸环化酶的抑制作用。Gpp(NH)p诱导的对福斯高林刺激的腺苷酸环化酶活性的抑制作用也不受锂盐治疗的影响。在任何研究条件下，[3H]福斯高林与大鼠大脑皮质的结合（假定与腺苷酸环化酶催化亚基和刺激性鸟嘌呤核苷酸结合调节蛋白（Gs）的活化复合物相关）均不受锂盐或抗抑郁药给药的影响。通过使用百日咳毒素（胰岛激活蛋白，IAP）催化的[32P]ADP - 核糖基化测定的对百日咳毒素敏感的G蛋白（Gi/Go）也不受锂盐或抗抑郁药治疗的影响。结合阐明这些抗精神病药物作用机制的观点，对这些结果的意义进行了讨论。
