Kim Airee, Mandyam Chitra D
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA.
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA.
Pharmacol Biochem Behav. 2014 Nov;126:90-6. doi: 10.1016/j.pbb.2014.09.012. Epub 2014 Sep 28.
Methamphetamine addicts demonstrate impaired frontal cortical-dependent cognitive function that could result from methamphetamine-induced maladaptive plasticity in the prefrontal cortex. Reduced adult gliogenesis observed in a rodent model of compulsive methamphetamine self-administration could contribute to the maladaptive plasticity in the medial prefrontal cortex (mPFC) as excessive methamphetamine intake is associated with loss of gliogenesis. The present study explored the vulnerability of mPFC progenitors to the duration of various sessions of methamphetamine self-administration in limited and extended access schedule of reinforcement. Proliferation of progenitors via Ki-67 labeling and apoptosis via activated caspase-3 labeling were studied in rats that intravenously self-administered methamphetamine in a limited access (1h/day: short access (ShA)) or extended access (6h/day: long access (LgA)) paradigm over 4, 13, 22 or 42 sessions, and in rats that experienced 22 sessions and were withdrawn from self-administration for a period of 4weeks. Four sessions of LgA methamphetamine enhanced proliferation and apoptosis and forty-two sessions of ShA and LgA methamphetamine reduced proliferation without effecting apoptosis. Withdrawal from twenty-two sessions of methamphetamine enhanced proliferation in LgA animals. Our findings demonstrate that proliferation of mPFC progenitors is vulnerable to psychostimulant exposure and withdrawal with distinct underlying mechanisms relating to methamphetamine toxicity. The susceptibility of mPFC progenitors to even modest doses of methamphetamine could account for the pronounced neuroadaptation in the mPFC linked to methamphetamine abuse.
甲基苯丙胺成瘾者表现出额叶皮质依赖的认知功能受损，这可能是由甲基苯丙胺引起的前额叶皮质适应性不良可塑性所致。在强迫性甲基苯丙胺自我给药的啮齿动物模型中观察到的成年期神经胶质生成减少，可能导致内侧前额叶皮质（mPFC）的适应性不良可塑性，因为过量摄入甲基苯丙胺与神经胶质生成丧失有关。本研究探讨了在有限和延长的强化给药时间表中，mPFC祖细胞对甲基苯丙胺自我给药不同疗程持续时间的易感性。通过Ki-67标记研究祖细胞的增殖，通过活化的caspase-3标记研究细胞凋亡，实验对象为在4、13、22或42个疗程中，以有限给药（每天1小时：短给药（ShA））或延长给药（每天6小时：长给药（LgA））模式静脉内自我给药甲基苯丙胺的大鼠，以及经历22个疗程并停止自我给药4周的大鼠。4个疗程的LgA甲基苯丙胺增强了增殖和凋亡，42个疗程的ShA和LgA甲基苯丙胺减少了增殖但不影响凋亡。停止22个疗程的甲基苯丙胺给药增强了LgA动物的增殖。我们的研究结果表明，mPFC祖细胞的增殖易受精神兴奋剂暴露和戒断的影响，其潜在机制与甲基苯丙胺毒性不同。mPFC祖细胞对即使适度剂量的甲基苯丙胺也敏感，这可能解释了与甲基苯丙胺滥用相关的mPFC中明显的神经适应性变化。
