Dazzi Laura, Seu Emanuele, Cherchi Giulia, Biggio Giovanni
Department of Experimental Biology "B Loddo", Unit of Neuropsychopharmacology, University of Cagliari, Cagliari, Italy.
Biol Psychiatry. 2004 Mar 1;55(5):477-83. doi: 10.1016/j.biopsych.2003.11.020.
Chronic exposure to stressful events precipitates or exacerbates many neuropsychiatric disorders, including depression and schizophrenia. Evidence suggests that treatment with the atypical antipsychotic drugs olanzapine or clozapine results in a superior amelioration of the anxious and depressive symptoms that accompany schizophrenia relative to therapy with classical antipsychotics such as haloperidol. Moreover, olanzapine and clozapine, but not haloperidol, increase the brain content of neuroactive steroids. The effects of olanzapine and clozapine on the stress-induced increase in dopamine output in the rat cerebral cortex have now been compared with that of haloperidol.
Rats chronically treated (3 weeks, once a day) with each drug were exposed to foot-shock stress or injected with a single dose of the anxiogenic benzodiazepine receptor ligand FG7142, and dopamine release was then measured in the prefrontal cortex by vertical microdialysis.
Long-term administration of olanzapine or clozapine prevented or markedly inhibited, respectively, the increase in the extracellular dopamine concentration induced by foot shock; haloperidol had no such effect. Chronic olanzapine treatment also blocked the effect of FG7142 on dopamine output.
The reduction in the sensitivity of cortical dopaminergic neurons to stress shown to be elicited by treatment with olanzapine or clozapine may contribute to the anxiolytic actions of these drugs.
长期暴露于应激事件会引发或加剧许多神经精神疾病，包括抑郁症和精神分裂症。有证据表明，与使用氟哌啶醇等经典抗精神病药物治疗相比，使用非典型抗精神病药物奥氮平或氯氮平治疗能更有效地改善精神分裂症伴随的焦虑和抑郁症状。此外，奥氮平和氯氮平能增加神经活性甾体的脑内含量，而氟哌啶醇则不能。现在已将奥氮平和氯氮平对大鼠大脑皮质应激诱导的多巴胺释放增加的影响与氟哌啶醇的影响进行了比较。
对用每种药物进行长期治疗（3周，每日一次）的大鼠施加足部电击应激，或注射单剂量的致焦虑苯二氮䓬受体配体FG7142，然后通过垂直微透析法测量前额叶皮质中的多巴胺释放。
长期给予奥氮平或氯氮平分别预防或显著抑制了足部电击诱导的细胞外多巴胺浓度增加；氟哌啶醇则无此作用。长期奥氮平治疗还阻断了FG7142对多巴胺释放的影响。
奥氮平或氯氮平治疗显示可引发皮质多巴胺能神经元对应激的敏感性降低，这可能有助于这些药物的抗焦虑作用。
