Impaired formation of stimulus-response, but not action-outcome, associations in rats with methamphetamine-induced neurotoxicity.
Impaired formation of stimulus-response, but not action-outcome, associations in rats with methamphetamine-induced neurotoxicity.
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大鼠中刺激反应形成受损，但行动结果与甲基苯丙胺诱导的神经毒性无关。
DOI：
10.1038/npp.2011.131
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Keefe,KristenA
中科院分区：
文献类型：
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作者：
Son,Jong-Hyun;Latimer,Christine;Keefe,KristenA
甲基苯丙胺（METH）诱导神经毒性变化，包括部分纹状体多巴胺耗竭，这被认为有助于啮齿动物和人类的认知功能障碍。背侧纹状体与工具性学习中的动作-结果（A-O）和刺激-反应（S-R）相关。因此，本研究探讨了长期的后果，甲硫氨酸诱导的神经毒性的A-O和S-R协会潜在的食欲工具行为。用生理盐水或METH（4× 7.5-10 mg/kg）的神经毒性方案预处理大鼠。随机比率（RR）或随机间隔（RI）强化时间表训练的大鼠，然后进行结果贬值或应急退化，然后通过灭绝测试。然后处死所有大鼠，取出大脑用于测定纹状体多巴胺损失。结果表明：（1）METH预处理可使背内侧和背外侧纹状体多巴胺组织含量减少45-50%，（2）METH诱导的神经毒性并不改变RR或RI时间表上工具性行为的获得，（3）结果贬值和应急降级同样降低了盐水和METH预处理大鼠在RR时间表上的反应，提示完整的A-O关联指导行为;（4）RI训练后的结果贬值仅在MET预处理的大鼠中降低消退反应，表明S-R关联受损。总的来说，这些数据表明，甲基苯丙胺诱导的神经毒性，可能是由于背外侧纹状体电路的功能受损，可能会降低认知灵活性，通过损害自动化行为模式的能力。
Methamphetamine (METH) induces neurotoxic changes, including partial striatal dopamine depletions, which are thought to contribute to cognitive dysfunction in rodents and humans. The dorsal striatum is implicated in action–outcome (A–O) and stimulus–response (S–R) associations underlying instrumental learning. Thus, the present study examined the long-term consequences of METH-induced neurotoxicity on A–O and S–R associations underlying appetitive instrumental behavior. Rats were pretreated with saline or a neurotoxic regimen of METH (4× 7.5–10 mg/kg). Rats trained on random ratio (RR) or random interval (RI) schedules of reinforcement were then subjected to outcome devaluation or contingency degradation, followed by an extinction test. All rats then were killed, and brains removed for determination of striatal dopamine loss. The results show that:(1) METH pretreatment induced a partial 45–50% decrease in striatal dopamine tissue content in dorsomedial and dorsolateral striatum;(2) METH-induced neurotoxicity did not alter acquisition of instrumental behavior on either RR or RI schedules;(3) outcome devaluation and contingency degradation similarly decreased responding in saline-and METH-pretreated rats trained on the RR schedule, suggesting intact A–O associations guiding behavior;(4) outcome devaluation after training on the RI schedule decreased extinction responding only in METH-pretreated rats, suggesting impaired S–R associations. Overall, these data suggest that METH-induced neurotoxicity, possibly due to impairment of the function of dorsolateral striatal circuitry, may decrease cognitive flexibility by impairing the ability to automatize behavioral patterns.