氯氮平和可卡因对精神刺激行为和戒断时伏隔核中多巴胺和血清素释放的影响。
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Broderick PA, Hope O, Okonji C, Rahni DN, Zhou Y
氯氮平和可卡因对精神刺激行为和戒断时伏隔核中多巴胺和血清素释放的影响。
《神经精神药理学生物精神病学进展》2004年1月28日(1):157-71。
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14687870 (PubMed视图］
- 摘要
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人们越来越意识到，一种类似于精神分裂症的精神病可以由可卡因成瘾引起。因此，用体内微伏安法研究了典型的非典型抗精神病药物氯氮平(5-HT (2)/DA(2)拮抗剂)对行为正常的雄性Sprague-Dawley实验室大鼠的伏隔核(NAcc)中可卡因诱导的多巴胺(DA)和血清素(5-HT)释放的影响，同时用红外光束监测动物的运动(向前走动)，一种a(10)行为。通过使用去极化阻滞剂γ -丁内酯(gammaBL)来确定单胺的释放机制。BRODERICK探针微电极选择性地检测DA和5-HT在几秒钟内的释放，并依次在A(10)神经末梢NAcc中释放。每个治疗组都进行了急性和亚急性研究。急性研究定义为在每种单胺和运动行为达到稳定基线后单次注射药物。亚急性研究被定义为对同一动物的每种单胺和运动行为进行24小时的随访研究，在此期间，不再给药。结果显示:(1)急性给药可卡因(10 mg/kg ip) (n=5)显著增加了DA和5- ht的释放(P<.001)，同时运动也显著增加了基线(P<.001)。在亚急性期研究中，DA的释放显著低于基线(P<.001)， 5-羟色胺的释放在第15分钟和该小时后半段的每个时间点均显著降低(P<.05);5-HT的最大降幅比基线低40%。 Locomotor behavior, on the other hand, increased significantly above baseline (P<.05). (2) Acute administration of clozapine/cocaine (20 and 10 mg/kg ip, respectively; n=6) produced a significant block of the cocaine-induced increase in DA (P<.001) and 5-HT release (P<.001). Cocaine-induced locomotion was blocked simultaneously with each monoamine by clozapine as well (P<.001). In subacute studies, DA release continued to be blocked presumably via clozapine by exhibiting a statistically significant decrease (P<.001), but 5-HT release increased significantly (P<.001), while cocaine-induced locomotor activity also continued to be antagonized by clozapine, i.e., locomotor activity exhibited no difference from baseline (P>.05). In summary, acute studies (a) support previous data from this laboratory and others that cocaine acts as a stimulant on the monoamines, DA and 5-HT and on locomotor behavior as well and (b) show that clozapine, 5-HT(2)/DA(2) antagonist, blocked enhanced DA, 5-HT and psychomotor stimulant behavior induced by cocaine. Subacute studies (a) suggest that withdrawal responses occurred in the cocaine group, based on recorded deficiencies in monoamine neurotransmitters (b) show that withdrawal effects in the cocaine group likely presynaptic, were distinguished from locomotor behavior, classically known to be mediated postsynaptically, and finally, (c) suggest that clozapine, with longer lived pharmacokinetic properties, reversed 5-HT cocaine-related withdrawal effects, but was unable to reverse DA cocaine-related withdrawal responses. Taken together with data from this laboratory, in which the 5-HT(2A/2C) antagonist, ketanserin, affected cocaine neurochemistry in much the same way as did clozapine, a mediation by either separate or combined 5-HT(2A/2C) receptors for these clozapine/cocaine interactions, is suggested. Further studies, designed to tease out the responses of selective 5-HT(2A) and 5-HT(2C) receptor compounds to cocaine and clozapine/cocaine, are underway.