Ichikawa Junji, Li Zhu, Dai Jin, Meltzer Herbert Y
Division of Psychopharmacology, Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37212, USA.
Brain Res. 2002 Nov 29;956(2):349-57. doi: 10.1016/s0006-8993(02)03570-9.
Preferential increases in both cortical dopamine (DA) and acetylcholine (ACh) release have been proposed to distinguish the atypical antipsychotic drugs (APDs) clozapine, olanzapine, risperidone and ziprasidone from typical APDs such as haloperidol. Although only clozapine and ziprasidone are directly acting 5-HT(1A) agonists, WAY100635, a selective 5-HT(1A) antagonist, partially attenuates these atypical APD-induced increases in cortical DA release that may be due to combined 5-HT(2A) and D(2) blockade. However, WAY100635 does not attenuate clozapine-induced cortical ACh release. The present study determined whether quetiapine, iloperidone and melperone, 5-HT(2A)/D(2) antagonist atypical APDs, also increase cortical DA and ACh release, and whether these effects are related to 5-HT(1A) agonism. Quetiapine (30 mg/kg), iloperidone (1-10 mg/kg), and melperone (3-10 mg/kg) increased DA and ACh release in the medial prefrontal cortex (mPFC). Iloperidone (10 mg/kg) and melperone (10 mg/kg), but not quetiapine (30 mg/kg), produced an equivalent or a smaller increase in DA release in the nucleus accumbens (NAC), respectively, compared to the mPFC, whereas none of them increased ACh release in the NAC. WAY100635 (0.2 mg/kg), which alone did not affect DA or ACh release, partially attenuated quetiapine (30 mg/kg)-, iloperidone (10 mg/kg)- and melperone (10 mg/kg)-induced DA release in the mPFC. WAY100635 also partially attenuated quetiapine (30 mg/kg)-induced ACh release in the mPFC, but not that induced by iloperidone (10 mg/kg) or melperone (10 mg/kg). These results indicate that quetiapine, iloperidone and melperone preferentially increase DA release in the mPFC, compared to the NAC via a 5-HT(1A)-related mechanism. However, 5-HT(1A) agonism may be important only for quetiapine-induced ACh release.
已有研究提出，皮质多巴胺（DA）和乙酰胆碱（ACh）释放的优先增加可将非典型抗精神病药物（APD）氯氮平、奥氮平、利培酮和齐拉西酮与典型APD（如氟哌啶醇）区分开来。虽然只有氯氮平和齐拉西酮是直接作用的5-HT(1A)激动剂，但选择性5-HT(1A)拮抗剂WAY100635可部分减弱这些非典型APD诱导的皮质DA释放增加，这可能是由于5-HT(2A)和D(2)联合阻断所致。然而，WAY100635并不减弱氯氮平诱导的皮质ACh释放。本研究确定了5-HT(2A)/D(2)拮抗剂非典型APD喹硫平、伊潘立酮和美哌隆是否也会增加皮质DA和ACh释放，以及这些作用是否与5-HT(1A)激动作用有关。喹硫平（30mg/kg）、伊潘立酮（1 - 10mg/kg）和美哌隆（3 - 10mg/kg）增加了内侧前额叶皮质（mPFC）中DA和ACh的释放。与mPFC相比，伊潘立酮（10mg/kg）和美哌隆（10mg/kg）分别使伏隔核（NAC）中DA释放增加量相当或更小，而喹硫平（30mg/kg）则未增加，且它们均未增加NAC中ACh的释放。单独使用不影响DA或ACh释放的WAY100635（0.2mg/kg）可部分减弱喹硫平（30mg/kg）、伊潘立酮（10mg/kg）和美哌隆（10mg/kg）诱导的mPFC中DA释放。WAY100635也可部分减弱喹硫平（30mg/kg）诱导的mPFC中ACh释放，但不能减弱伊潘立酮（10mg/kg）或美哌隆（10mg/kg）诱导的ACh释放。这些结果表明，喹硫平、伊潘立酮和美哌隆通过与5-HT(1A)相关的机制，与NAC相比，优先增加mPFC中DA的释放。然而，5-HT(1A)激动作用可能仅对喹硫平诱导的ACh释放起重要作用。
