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mGluR5 involvement in methamphetamine reward and the co-morbidity of schizophrenia and stimulant use disorders.

机译：mGluR5参与了甲基苯丙胺奖赏以及精神分裂症和兴奋剂使用障碍的合并症。

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摘要

Methamphetamine (Meth) is a potent, widely-used stimulant. Stimulant abuse occurs more frequently in the schizophrenia patient population than the general population. The co-morbidity of stimulant use disorders and schizophrenia presents an understudied phenomenon and suggests overlapping brain states of these two pathologies.;There are currently no FDA-approved pharmacotherapies for Meth addiction and relapse to Meth use remains a substantial challenge for abstinent Meth addicts. One factor that contributes to craving and relapse is exposure to environmental or contextual cues associated with Meth use. This effect is the consequence of associative learning that occurs between the rewarding properties of drugs and drug-related, contextual cues that become extremely salient to an individual. This drug-induced associative learning can be studied in the laboratory with humans and rodents using conditioned place preference (CPP). In the laboratory, repeated Meth administration also produces a progressive enhancement in motor activity termed motor sensitization. It is hypothesized that the neuronal adaptations associated with motor sensitization may model aspects of the brain changes that are associated with Meth abuse in humans. Schizophrenia patients and rodent models of the disorder demonstrate deficits in sensorimotor gating, or the inability to properly filter sensory information properly. Sensorimotor gating deficits are measured in the laboratory through the use of pre-pulse inhibition (PPI) of the acoustic startle response. PPI is defined as a normal suppression of the startle response when a weaker acoustic stimulus is presented before a louder startling acoustic stimulus. The current dissertation project utilized Meth-induced CPP, motor sensitization, and PPI to elucidate neuronal underpinnings of Meth addiction and schizophrenia / Meth addiction co-morbidity.;The glutamate transmitter system is important for memory processing, addiction, and the neuropathology of schizophrenia. Glutamate activates both ionotropic and metabotropic receptors; the group I subtype 5 metabotropic glutamate receptor (mGluR5) is highly expressed in brain regions known to be important for stimulant reward. Thus, mGluR5 functions to fine tune neuronal excitability and modulate drug-induced behaviors. It is important, and clinically relevant, to study the neuronal adaptations that occur following repeated Meth administration in order to evaluate the ability of potential pharmacotherapy targets to influence Meth-induced behaviors in the general and schizophrenia patient population.;The goal of this dissertation project was to elucidate the role of mGluR5 in different phases of Meth-induced associative learning in normal and schizophrenia-like rodents and to determine the correlation between deficits associated with schizophrenia and responding to the rewarding effects of Meth.
机译：甲基苯丙胺（甲基）是一种有效的，广泛使用的兴奋剂。精神分裂症患者人群中的刺激性滥用比普通人群更为频繁。兴奋剂使用障碍和精神分裂症的合并症呈现出一种未被充分研究的现象，并提示这两种病理的大脑状态重叠。;目前，尚无FDA批准的用于药物成瘾和复发使用药物的药物疗法仍然是禁欲的成瘾者的一大挑战。导致渴望和复发的一个因素是暴露于与使用甲基溴相关的环境或上下文提示。这种影响是在药物的奖励性质与与药物相关的，对个人极为重要的上下文提示之间发生关联学习的结果。这种药物诱导的联想学习可以在人类和啮齿动物中使用条件位置偏好（CPP）在实验室中进行研究。在实验室中，反复服用甲基苯丙氨酸还可以使运动活动逐渐增强，称为运动致敏作用。假设与运动敏化相关的神经元适应可以模拟与人类中的甲基苯丙胺滥用相关的大脑变化的各个方面。精神分裂症患者和该疾病的啮齿动物模型表现出感觉运动门控功能缺陷，或无法正确过滤感觉信息。感觉运动门控缺陷在实验室中通过使用声惊吓反应的预脉冲抑制（PPI）进行测量。 PPI被定义为在响亮的震撼性听觉刺激之前出现较弱的听觉刺激时对惊吓反应的正常抑制。当前的研究项目利用了由甲基引起的CPP，运动致敏和PPI来阐明甲基成瘾和精神分裂症/甲基成瘾合并症的神经基础。谷氨酸递质系统对于记忆处理，成瘾和精神分裂症的神经病理学非常重要。谷氨酸激活离子型和代谢型受体。 I类5型代谢型谷氨酸受体（mGluR5）在已知对刺激奖励很重要的大脑区域中高表达。因此，mGluR5的功能是微调神经元兴奋性和调节药物诱导的行为。研究重复服用甲基安非他明后发生的神经元适应性，以评估潜在的药物治疗靶标影响普通和精神分裂症患者人群中由甲基安非他明引起的行为的能力是重要的，并且在临床上具有相关性。阐明mGluR5在正常和精神分裂症样啮齿动物中由甲基诱导的联想学习的不同阶段中的作用，并确定与精神分裂症相关的缺陷与对甲基利弊的反应之间的相关性。

著录项

  • 作者

    Herrold, Amy Anne.;

  • 作者单位

    Loyola University Chicago.;

  • 授予单位 Loyola University Chicago.;
  • 学科 Neurosciences.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 249 p.
  • 总页数 249
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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