Robinson T E, Jurson P A, Bennett J A, Bentgen K M
Department of Psychology, University of Michigan, Ann Arbor 48109.
Brain Res. 1988 Oct 18;462(2):211-22. doi: 10.1016/0006-8993(88)90549-5.
In humans the repeated use of amphetamine (AMPH) produces a hypersensitivity to the psychotogenic effects of AMPH that persists for months to years after the cessation of drug use. To explore the neurobiological basis of this phenomenon the long-term effects of dextroamphetamine [+)-AMPH) on brain monoamines and behavior were studied in an animal model of AMPH psychosis. An escalating dose pretreatment regimen (from 1 to 10 mg/kg over 5 weeks) was used to mimic the pattern of drug use associated with the development of addiction and AMPH psychosis. The effect of pretreatment with AMPH on dopamine (DA) release in the ventral striatum (nucleus accumbens) was determined by measuring the extracellular concentrations of DA and DA metabolites using in vivo microdialysis, both before and after an AMPH challenge. The postmortem tissue concentrations of DA, serotonin and their metabolites were measured to determine if this treatment was neurotoxic. Escalating doses of (+)-AMPH were not neurotoxic, and 25-30 days after the cessation of drug treatment animals showed relatively normal levels of spontaneous motor activity across the day-night cycle. However, AMPH pretreatment produced robust behavioral sensitization. Animals showed a marked hypersensitivity to the motor stimulant effects of an AMPH challenge, even after 15-20 days of withdrawal. Most importantly, this hyperdopaminergic behavioral syndrome was accompanied by significantly elevated DA release in the ventral striatum. In contrast, AMPH pretreatment had no effect on the basal extracellular concentrations of DA.(ABSTRACT TRUNCATED AT 250 WORDS)
在人类中，反复使用苯丙胺（AMPH）会导致对AMPH的致幻作用产生超敏反应，这种反应在停止使用药物后的数月至数年中持续存在。为了探究这一现象的神经生物学基础，在AMPH精神病的动物模型中研究了右旋苯丙胺[（+）-AMPH]对脑单胺和行为的长期影响。采用递增剂量预处理方案（在5周内从1毫克/千克增至10毫克/千克）来模拟与成瘾和AMPH精神病发展相关的药物使用模式。通过在AMPH激发前后使用体内微透析测量多巴胺（DA）及其代谢产物的细胞外浓度，来确定AMPH预处理对腹侧纹状体（伏隔核）中DA释放的影响。测量死后组织中DA、5-羟色胺及其代谢产物的浓度，以确定这种处理是否具有神经毒性。递增剂量的（+）-AMPH并无神经毒性，在停止药物治疗25 - 30天后，动物在昼夜周期中表现出相对正常的自发运动活动水平。然而，AMPH预处理产生了强烈的行为敏化。即使在戒断15 - 20天后，动物对AMPH激发的运动刺激作用仍表现出明显的超敏反应。最重要的是，这种高多巴胺能行为综合征伴随着腹侧纹状体中DA释放的显著升高。相比之下，AMPH预处理对DA的基础细胞外浓度没有影响。（摘要截短于250字）
