Schwieler Lilly, Erhardt Sophie
Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
Neuropsychopharmacology. 2003 Oct;28(10):1770-7. doi: 10.1038/sj.npp.1300255.
The mode of action by which the atypical antipsychotic drug clozapine exerts its superior efficacy to ameliorate both positive and negative symptoms is still unknown. In the present in vivo electrophysiological study, we investigate the effects of haloperidol (a typical antipsychotic drug) and clozapine on ventral tegmental area (VTA) dopamine (DA) neurons in a situation of hyperdopaminergic activity in order to mimic tentatively a condition similar to that seen in schizophrenia. Increased DA transmission was induced by elevating endogenous levels of the N-methyl-D-aspartate receptor and alpha7(*) nicotinic receptor antagonist kynurenic acid (KYNA; by means of PNU 156561A, 40 mg /kg, i.v.). In control rats, i.v. administered haloperidol (0.05-0.8 mg/kg) or clozapine (1.25-10 mg/kg) was associated with increased firing rate and burst firing activity of VTA DA neurons. However, in rats displaying hyperdopaminergia (induced by elevated levels of KYNA), the effects of clozapine on VTA DA neurons were converted into pure inhibitory responses, including decrease in burst firing activity. In contrast, haloperidol still produced an excitatory action on VTA DA neurons in rats with elevated levels of endogenous brain KYNA. The results of the present study suggest that clozapine facilitates or inhibits VTA DA neurotransmission, depending on brain concentration of KYNA. Such an effect of clozapine may be related to its unique effect in also ameliorating negative symptoms of schizophrenia.
非典型抗精神病药物氯氮平发挥其改善阳性和阴性症状的卓越疗效的作用方式仍然未知。在目前的体内电生理学研究中，我们研究了氟哌啶醇（一种典型抗精神病药物）和氯氮平在多巴胺能活性亢进情况下对腹侧被盖区（VTA）多巴胺（DA）神经元的影响，以便初步模拟类似于精神分裂症所见的状况。通过提高内源性N-甲基-D-天冬氨酸受体和α7（*）烟碱受体拮抗剂犬尿喹啉酸（KYNA；借助于PNU 156561A，40mg/kg，静脉注射）的水平来诱导多巴胺传递增加。在对照大鼠中，静脉注射氟哌啶醇（0.05 - 0.8mg/kg）或氯氮平（1.25 - 10mg/kg）与VTA DA神经元的放电频率增加和爆发式放电活动增加相关。然而，在表现出多巴胺能亢进（由KYNA水平升高诱导）的大鼠中，氯氮平对VTA DA神经元的作用转变为纯粹的抑制性反应，包括爆发式放电活动的减少。相比之下，氟哌啶醇在脑内KYNA水平升高的大鼠中仍对VTA DA神经元产生兴奋作用。本研究结果表明，氯氮平促进或抑制VTA DA神经传递，这取决于脑内KYNA的浓度。氯氮平的这种作用可能与其在改善精神分裂症阴性症状方面的独特作用有关。
