Westerink B H, de Boer P, de Vries J B, Kruse C G, Long S K
University Center for Pharmacy, Department of Medicinal Chemistry, Groningen, The Netherlands.
Eur J Pharmacol. 1998 Nov 13;361(1):27-33. doi: 10.1016/s0014-2999(98)00711-0.
In the present study we have compared the effects of the classical antipsychotic drug haloperidol and four different atypical antipsychotics (clozapine, risperidone, olanzapine, ziprasidone) on extracellular levels of dopamine and noradrenaline in the medial prefrontal cortex (MPFC) of conscious rats. Haloperidol (10, 100 and 800 nmol/kg), clozapine (0.3, 1, 10 and 30 micromol/kg), risperidone (100, 500 and 5000 nmol/kg), olanzapine (10, 100 and 500 nmol/kg) and ziprasidone (10, 100 and 1000 nmol/kg) were administered subcutaneously to rats. All compounds induced increases in dialysate levels of dopamine and noradrenaline in the medial prefrontal cortex. The increases induced by the four antipsychotic agents in extracellular levels of dopamine and noradrenaline displayed a striking co-variation both in dose and time. A similar co-variation was seen in the decrease of dopamine and noradrenaline, after administration of a low dose (30 nmol/kg, s.c.) of the dopamine D2/3 receptor agonist (+)-7-hydroxy-2-(N,N-di-n-propylamino) tetralin ((+)-7-OH-DPAT). It is concluded that there is a close coupling between the release of dopamine and noradrenaline in the medial prefrontal cortex. The mechanism of action of this interaction, that might be of importance for a better understanding of the mechanism of action of antipsychotic drugs, is discussed.
在本研究中，我们比较了经典抗精神病药物氟哌啶醇和四种不同的非典型抗精神病药物（氯氮平、利培酮、奥氮平、齐拉西酮）对清醒大鼠内侧前额叶皮质（MPFC）中多巴胺和去甲肾上腺素细胞外水平的影响。将氟哌啶醇（10、100和800 nmol/kg）、氯氮平（0.3、1、10和30 μmol/kg）、利培酮（100、500和5000 nmol/kg）、奥氮平（10、100和500 nmol/kg）和齐拉西酮（10、100和1000 nmol/kg）皮下注射给大鼠。所有化合物均导致内侧前额叶皮质透析液中多巴胺和去甲肾上腺素水平升高。四种抗精神病药物引起的多巴胺和去甲肾上腺素细胞外水平升高在剂量和时间上均呈现出显著的共变关系。在给予低剂量（30 nmol/kg，皮下注射）的多巴胺D2/3受体激动剂（+）-7-羟基-2-（N，N-二正丙基氨基）四氢萘（（+）-7-OH-DPAT）后，多巴胺和去甲肾上腺素的降低也出现了类似的共变关系。得出的结论是，内侧前额叶皮质中多巴胺和去甲肾上腺素的释放之间存在紧密的耦合。讨论了这种相互作用的作用机制，这可能有助于更好地理解抗精神病药物的作用机制。
