An experimental study on relapse of schizophrenia - A biochemical study using methamphetamine psychosis

滥用安非他明(AMP)或甲基苯丙胺(MAP)等精神刺激剂会产生类似于偏执型精神分裂症的精神病。同样，对实验动物亚慢性给予AMP或MAP可诱导行为敏化，其中在亚慢性治疗停止后给予这些药物的激发剂量可以诱导增强的行为反应。本研究旨在探讨行为敏化的机制，包括两个实验。在亚慢性MAP治疗后的稳态条件下，观察细胞内外Na+浓度梯度对纹状体多巴胺(DA)外流的影响。大鼠每日注射MAP或生理盐水4 mg/kg，连续14天。最后一次注射后7天，通过纹状体内的半透性探头局部注入哇巴因，这是一种选择性的Na^+，K^+-ATPase抑制剂。哇巴因诱导的I-…显著增加亚慢性MAP组纹状体灌流液中DA浓度较对照组升高更明显。与MAP组相比，利血平预处理对哇巴因诱导的亚慢性MAP的DA外流无明显影响。相反，甲基对酪氨酸预处理可阻断哇巴因引起的DA外流。这些结果表明，亚慢性MAP处理促进了新合成的DA的外流，这种外流是由哇巴因引起细胞内和细胞外介质之间的Na+梯度降低所引起的。实验大鼠出生后7、14、21、28、56日龄，分别给予MAP 2 mg/kg和4 mg/kg，每日2次，连续3天。对照组大鼠按相同程序给予等体积生理盐水。在末次预处理后21天给予MAP刺激，仅在PND 21、28和56开始时，MAP预处理组大鼠细胞外DA水平显著高于对照组大鼠，而在年轻大鼠中则没有。相应地，MAP诱导的刻板行为只有在PND 21、28和56开始时才显著增强，而在PND 7和14上没有。这些结果表明MAP诱导的行为敏感化和释放DA的潜在能力在PND 21或其周围被建立。较少

Abuse of psychostimulants such as amphetamine (AMP) or methamphetamine (MAP) can produce psychosis, which resembles paranoid schizophrenia. Similarly, subchronic administration of AMP or MAP to experimental animals induces behavioral sensitization, in which augmented behavioral responses can be induced by administration of challenge doses of these drugs after cessation of subchronic treatment. The present study was conducted to investigate the mechanism of behavioral sensitization, and consists of two experiments.1. The effect of manipulation of Na^+ gradient between the intracellular and extracellular media on striatal dopamine (DA) efflux under steady-state conditions after subchronic MAP treatment was investigated. Rats were injected with 4 mg/kg MAP or saline once daily for 14 days. Seven days after the last injection, ouabain, a selective inhibitor of the Na^+, K^+-ATPase, was infused locally through a semi-permeable probe in the striatum. Ouabain induced a significantly greater i … More ncrease of the DA concentrations in the striatal perfusate in the subchronic MAP than the control group. Reserpine pretreatment did not affect the enhanced ouabain-induced DA efflux in the subchronic MAP than in the MAP group. In contrast, -methyl-p-tyrosine pretreatment abolished the ouabain-induced efflux of DA in both groups. These results suggest that subchronic MAP treatment facilitates the efflux of newly synthesized DA, which is induced by the ouabain-induced decrease of the Na^+ gradient between intracellular and extracellular media.2. Experimental rats aged 7, 14, 21, 28, 56 postnatal days (PNDs) were pretreated twice daily with 2 mg/kg MAP for 3 days followed by 4 mg/kg for 3 days. Matched control rats were given equivalent volumes of saline according to the same schedule. The MAP challenge, given 21 days after the last pretreatment, induced significantly greater increases in extracellular DA levels in the MAP-pretreated rats compared with control rats only when MAP pretreatment was initiated on PNDs 21, 28 and 56, but not in younger rats. Correspondingly, MAP-induced stereotyped behavior was enhanced significantly only when MAP pretreatment was started on PNDs 21, 28 and 56, but not PNDs 7 and 14. These results suggest that MAP-induced behavioral sensitization and the underlying ability to release DA is established on or around PND 21. Less