Clozapine, haloperidol, and the D4 antagonist PNU-101387G:: in vivo effects on mesocortical, mesolimbic, and nigrostriatal dopamine and serotonin release
Clozapine, haloperidol, and the D4 antagonist PNU-101387G:: in vivo effects on mesocortical, mesolimbic, and nigrostriatal dopamine and serotonin release
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DOI：
10.1007/s007020050093
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发表时间：
1998-01-01
影响因子：
3.3
通讯作者：
Piercey, MF
中科院分区：
文献类型：
--
作者：
Broderick, PA;Piercey, MF
采用体内微伏安法，评价了多巴胺（DA）受体拮抗剂氯氮平（D-4/D-2）、氟哌啶醇（D-2）和选择性D-4拮抗剂pnu101387g对水合氯醛麻醉大鼠A（10）神经元末端场[中脑皮层、前额叶皮层（PFC）、中脑边缘、伏隔核（NAcc）]和A(9)神经元末端场[黑纹状体、尾状壳核（CPU）]内DA和5-羟色胺（5-HT）释放的影响。氯氮平也具有5-HT2受体拮抗剂的特性，显著（p < 0.001）增加了A（10）末端区、PFC和NAcc内DA的释放；氯氮平在A、末端、CPU内不增加DA的释放。氯氮平在A（10）和A(9)末端区显著提高血清素释放量（p < 0.001）。氟哌啶醇显著（p < 0.001）增加了PFC内DA的释放量，显著且显著（p < 0.001）增加了CPU内DA的释放量，但没有增加NAcc内DA的释放量；氟哌啶醇在PFC内[仅在最高剂量（2.5 mg/kg）时]和在CPU内[仅在最低剂量（1.0 mg/kg）时]的5-HT释放量虽小但有统计学意义（p < 0.05）。选择性D-4拮抗剂PNU-101387G显著增加PFC内DA释放量（p < 0.001），适度增加CPU内DA释放量（p < 0.001）。在最低剂量（1.0 mg/kg）下未改变DA在NAcc内的释放，而在最高剂量（1.0 mg/kg）下显著（p < 0.05）降低了DA在NAcc内的释放。选择性D-4拮抗剂不影响A（10）或A(9)末端域内5-HT的释放。本文从氯氮平和氟哌啶醇的神经化学、抗精神病活性和副作用方面进行了讨论，以便为选择性D-4拮抗剂PNU-101387G提供比较资料。
With in vivo microvoltammetry, the dopamine (DA) receptor antagonists, clozapine (D-4/D-2), haloperidol (D-2) and the selective D-4 antagonist, PNU-101387G, were evaluated for their effects on DA and serotonin (5-HT) release within A(10) neuronal terminal fields [mesocortical, prefrontal cortex (PFC), mesolimbic, nucleus accumbens, (NAcc)] and within A(9) neuronal terminal fields [nigrostriatal, caudate putamen (CPU)], in chloral hydrate anesthetized rats. Clozapine, which also has 5-HT2 receptor antagonist properties, significantly (p < 0.001) increased DA release within A(10) terminal fields, PFC and NAcc; DA release was not increased by clozapine within A, terminals, CPU. Serotonin release was significantly (p < 0.001) increased by clozapine within A(10) and A(9) terminal fields. Haloperidol significantly (p < 0.001) increased DA release within PFC, dramatically and significantly (p < 0.001) increased DA release within CPU, but not within NAcc; haloperidol had a small but statistically significant (p < 0.05) increase on 5-HT release within PFC [only at the highest dose studied (2.5 mg/kg)] and within CPU [only at the lowest dose studied 1.0 mg/kg) (p < 0.05)]. The selective D-4 antagonist, PNU-101387G dramatically and significantly (p < 0.001) increased DA release within PFC, modestly, but significantly (p < 0.001) increased DA release within CPU. did not alter DA release within NAcc at the lowest dose studied (1.0 mg/kg) and significantly (p < 0.05) decreased DA release within NAcc at the highest dose studied (1.0 mg/kg). The selective D-4 antagonist did not affect 5-HT release within either A(10) or A(9) terminal fields. The present data are discussed in terms of the neurochemistry, antipsychotic activity, and side effect profiles of clozapine and haloperidol, in order to provide comparative profiles for a selective D-4 antagonist, PNU-101387G.