Herrick-Davis K, Grinde E, Teitler M
Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York, USA.
J Pharmacol Exp Ther. 2000 Oct;295(1):226-32.
Clozapine is the prototype atypical antipsychotic drug, producing little or no extrapyramidal side effects, while improving negative symptoms of psychosis. Clozapine's high affinity for serotonin receptors has been hypothesized to confer the unique antipsychotic properties of this drug. Recently, we demonstrated that both typical and atypical antipsychotic drugs are inverse agonists at constitutively active 5-hydroxytryptamine2A (5-HT(2A)) receptors. To determine whether inverse agonist activity at 5-HT(2C) receptors plays a role in antipsychotic efficacy, typical and atypical antipsychotic drugs were tested for inhibition of basal inositol phosphate production in mammalian cells expressing rat or human 5-HT(2C) receptors. Atypical antipsychotic drugs (sertindole, clozapine, olanzapine, ziprasidone, risperidone, zotepine, tiospirone, fluperlapine, tenilapine) displayed potent inverse agonist activity at rat and human 5-HT(2C) receptors. Typical antipsychotic drugs (chlorpromazine, loxapine, thioridazine, prochlorperazine, perphenazine, mesoridazine, trifluperidol, fluphenazine, spiperone, haloperidol, pimozide, penfluridol, thiothixene) were devoid of inverse agonist activity, with the exception of loxapine. We review the evidence that loxapine has unique properties characteristic of both atypical and typical antipsychotic drugs. Several typical antipsychotic drugs (chlorpromazine, thioridazine, spiperone, thiothixene) displayed neutral antagonist activity by reversing clozapine inverse agonism. These data suggest that 5-HT(2C) inverse agonist activity is associated with atypical antipsychotic drugs with moderate to high affinity for 5-HT(2C) receptors, and imply that effects of atypical antipsychotic drugs on the 5-HT(2C) receptor may play a role in their unique clinical properties. These data also imply that dysfunction of brain 5-HT(2C) receptor systems may be one of the factors involved in the etiology of psychosis.
氯氮平是非典型抗精神病药物的原型，几乎不产生锥体外系副作用，同时能改善精神病的阴性症状。据推测，氯氮平对5-羟色胺受体的高亲和力赋予了该药物独特的抗精神病特性。最近，我们证明典型和非典型抗精神病药物都是组成型活性5-羟色胺2A（5-HT(2A)）受体的反向激动剂。为了确定5-HT(2C)受体的反向激动剂活性是否在抗精神病疗效中起作用，对典型和非典型抗精神病药物进行了测试，以检测其对表达大鼠或人类5-HT(2C)受体的哺乳动物细胞中基础肌醇磷酸生成的抑制作用。非典型抗精神病药物（舍吲哚、氯氮平、奥氮平、齐拉西酮、利培酮、佐替平、替螺酮、氟哌拉平、替萘哌汀）在大鼠和人类5-HT(2C)受体上表现出强效的反向激动剂活性。典型抗精神病药物（氯丙嗪、洛沙平、硫利达嗪、丙氯拉嗪、奋乃静、美索达嗪、三氟哌多、氟奋乃静、螺哌隆、氟哌啶醇、匹莫齐特、五氟利多、硫杂蒽酮）除洛沙平外均无反向激动剂活性。我们回顾了洛沙平具有非典型和典型抗精神病药物独特特性的证据。几种典型抗精神病药物（氯丙嗪、硫利达嗪、螺哌隆、硫杂蒽酮）通过逆转氯氮平的反向激动作用表现出中性拮抗剂活性。这些数据表明，5-HT(2C)反向激动剂活性与对5-HT(2C)受体具有中度至高亲和力的非典型抗精神病药物有关，这意味着非典型抗精神病药物对5-HT(2C)受体的作用可能在其独特的临床特性中发挥作用。这些数据还意味着脑5-HT(2C)受体系统功能障碍可能是精神病病因中的因素之一。
