Ichikawa J, Kuroki T, Dai J, Meltzer H Y
Department of Psychiatry, Vanderbilt University School of Medicine, The Psychiatric Hospital at Vanderbilt, Nashville, TN 37212, USA.
Eur J Pharmacol. 1998 Jun 19;351(2):163-71. doi: 10.1016/s0014-2999(98)00308-2.
Amperozide, clozapine, olanzapine and risperidone are more potent serotonin (5-hydroxytryptamine, 5-HT)2A receptor antagonists than dopamine D2-like receptor antagonists. Haloperidol and S(-)-sulpiride are potent or selective dopamine D2-like receptor antagonists and lack 5-HT2A receptor antagonist properties. We studied the effect of these five proven antipsychotic drugs and one putative (amperozide) antipsychotic drug on extracellular 5-HT levels in the medial prefrontal cortex and the nucleus accumbens of awake, freely-moving rats, using in vivo microdialysis with dual probe implantation. Risperidone (1 mg/kg) and clozapine (20 mg/kg) significantly increased extracellular 5-HT levels in the medial prefrontal cortex and the nucleus accumbens, respectively. Amperozide (2 and 10 mg/kg) significantly increased extracellular 5-HT levels in both regions. Olanzapine (1 and 10 mg/kg), S(-)-sulpiride (10 and 25 mg/kg), haloperidol (0.1 and 1 mg/kg) and the selective 5-HT2A receptor antagonist MDL-100,907 (1 mg/kg) had no significant effect on extracellular 5-HT levels in either region. Thus, the ability to increase extracellular 5-HT levels in the medial prefrontal cortex and the nucleus accumbens by these antipsychotic drugs is not directly related to their affinity for 5-HT2A receptors since olanzapine and MDL-100,907 had no significant effect on extracellular 5-HT levels. A variety of mechanisms other than those involving 5-HT2A receptors, e.g., reuptake inhibition (amperozide) and blockade of alpha2-adrenoceptors (clozapine), may contribute to the ability to increase extracellular 5-HT levels in the brain. The increase in extracellular 5-HT levels in the medial prefrontal cortex or nucleus accumbens following amperozide, clozapine, or risperidone administration may not be related to the effect on psychotic symptoms but could be related to effects on other types of psychopathology such as depression, negative symptoms, or cognition.
氨哌齐特、氯氮平、奥氮平和利培酮作为5-羟色胺（5-HT）2A受体拮抗剂，比多巴胺D2样受体拮抗剂的作用更强。氟哌啶醇和S(-)-舒必利是强效或选择性多巴胺D2样受体拮抗剂，不具备5-HT2A受体拮抗剂特性。我们使用双探针植入体内微透析技术，研究了这五种已证实的抗精神病药物和一种假定的（氨哌齐特）抗精神病药物对清醒、自由活动大鼠内侧前额叶皮质和伏隔核细胞外5-HT水平的影响。利培酮（1毫克/千克）和氯氮平（20毫克/千克）分别显著提高了内侧前额叶皮质和伏隔核的细胞外5-HT水平。氨哌齐特（2毫克/千克和10毫克/千克）显著提高了两个区域的细胞外5-HT水平。奥氮平（1毫克/千克和10毫克/千克）、S(-)-舒必利（10毫克/千克和25毫克/千克）、氟哌啶醇（0.1毫克/千克和1毫克/千克）以及选择性5-HT2A受体拮抗剂MDL-100,907（1毫克/千克）对两个区域的细胞外5-HT水平均无显著影响。因此，这些抗精神病药物提高内侧前额叶皮质和伏隔核细胞外5-HT水平的能力与其对5-HT2A受体的亲和力并无直接关系，因为奥氮平和MDL-100,907对细胞外5-HT水平无显著影响。除了涉及5-HT2A受体的机制外，其他多种机制，如再摄取抑制（氨哌齐特）和α2肾上腺素能受体阻断（氯氮平），可能有助于提高大脑中细胞外5-HT水平。服用氨哌齐特、氯氮平或利培酮后，内侧前额叶皮质或伏隔核细胞外5-HT水平的升高可能与对精神病症状的影响无关，但可能与对其他类型精神病理学的影响有关，如抑郁症、阴性症状或认知功能。
