Knable M B, Weinberger D R
National Institute of Mental Health, Clinical Brain Disorders Branch, St. Elizabeths Hospital, Washington, D.C. 20032.
J Clin Psychiatry. 1994 Sep;55 Suppl B:70-3.
The mechanisms of the antipsychotic efficacy and side effect profile of clozapine are incompletely understood. In vivo pharmacologic studies suggest that while clozapine does produce D2 receptor blockade, its unusual clinical profile may relate to activity at other receptor sites and to anatomical areas outside the striatum. Rodent studies indicate that acute administration of clinical doses of antipsychotic drugs, including clozapine, induces Fos (the protein product of the immediate early gene, c-fos) in the nucleus accumbens. However, unlike typical antipsychotic drugs, clozapine does not induce Fos in the dorsal striatum and does induce Fos in medial portions of the prefrontal cortex. Clozapine seems to produce a unique signature effect on long-term neuronal metabolism in its induction of Fos in the shell of the nucleus accumbens and in the medial prefrontal cortex. Future in vivo studies of cerebral blood flow and glucose metabolism in human patients may help to elucidate the specificity and reproducibility of the effects of clozapine in the ventral striatum and prefrontal cortex.
氯氮平抗精神病疗效及副作用的机制尚未完全明确。体内药理学研究表明，虽然氯氮平确实会产生D2受体阻断作用，但其独特的临床特征可能与其他受体部位及纹状体以外解剖区域的活性有关。啮齿动物研究表明，急性给予临床剂量的抗精神病药物，包括氯氮平，会在伏隔核中诱导Fos（即刻早期基因c-fos的蛋白质产物）。然而，与典型抗精神病药物不同，氯氮平不会在背侧纹状体中诱导Fos，而是会在前额叶皮质内侧部分诱导Fos。氯氮平在伏隔核壳和内侧前额叶皮质中诱导Fos时，似乎对长期神经元代谢产生独特的标志性作用。未来对人类患者进行的脑血流量和葡萄糖代谢的体内研究，可能有助于阐明氯氮平在腹侧纹状体和前额叶皮质中作用的特异性和可重复性。
