Drugs of abuse drive transmitter switching that causes drug-induced behavior

项目概要摘要： 反复接触滥用药物可能会导致成瘾，这是一种慢性且复发的疾病。 疾病被定义为寻求和服用药物的冲动，对限制摄入量失去控制， 以及消极情绪状态的出现。从吸毒到成瘾的转变包括 与奖赏、冲动控制和情感相关的大脑回路的神经可塑性。大脑区域之一是 因药物摄入而功能受损的是前额叶皮层 (PFC)，滥用药物会导致前额叶皮层的功能发生改变。 似乎与药物摄入失控密切相关的活动。增加我们的知识 滥用药物影响这些回路的方式对于更好地理解其机制非常重要 是向成瘾过渡的基础，并允许开发新的干预措施和治疗方法。 大脑回路的正常功能依赖于神经传递的正确规范和编排。 最近越来越多的证据表明，当长期的环境刺激产生 部分神经元的电活动持续改变，这些神经元可以经历 它们表达的神经递质的重新指定，通常导致从兴奋性转变为兴奋性 抑制性递质，反之亦然。这种新近被认识的神经可塑性形式，称为神经递质 转换，已在成年哺乳动物大脑中反复观察到，并与 动物行为。 我们假设反复接触滥用药物会引起神经递质转换，从而反过来 有助于建立药物引起的行为改变，例如认知缺陷、行为缺陷 致敏和药物诱导的强化。有两个具体目标将检验这一假设。第一具体目标 将测试 PCP 或 METH 的亚慢性治疗是否会诱导 PFC 中的神经递质转换。的 第二个具体目标将确定神经递质转换和药物之间是否存在因果关系 诱发的行为改变，包括认知缺陷、行为敏感化和药物引起的 加固。

Project Summary Abstract: Repeated exposure to a drug of abuse can lead to the development of an addiction, a chronic and relapsing illness that has been defined as the compulsion to seek and take the drug, the loss of control in limiting intake, and the emergence of a negative emotional state. The transition from drug intake to addiction involves neuroplasticity of brain circuits related to reward, impulse control and affect. One of the brain regions that is functionally impaired by drug intake is the prefrontal cortex (PFC), in which drugs of abuse induce alterations in activity that seem to be crucially involved in the loss of control over drug intake. Increasing our knowledge of the ways in which drugs of abuse impact these circuits is important to better understand the mechanisms underlying the transition to addiction and to allow the development of novel interventions and treatment. The proper function of brain circuits relies on the correct specification and orchestration of neurotransmission. Accumulating evidence has recently established that when prolonged environmental stimuli produce a sustained alteration in the electrical activity of a subset of neurons, these neurons can undergo a respecification of the neurotransmitter they express, often resulting in a switch from an excitatory to an inhibitory transmitter or vice versa. This newly appreciated form of neuroplasticity, called neurotransmitter switching, has been repeatedly observed in the adult mammalian brain and associated with alterations in animal behavior. We hypothesize that repeated exposure to drugs of abuse can induce neurotransmitter switching that in turn contributes to the establishment of drug-induced behavioral alterations such as cognitive deficits, behavioral sensitization and drug-induced reinforcement. Two specific aims will test this hypothesis. The 1st specific aim will test whether sub-chronic treatment with PCP or METH induces neurotransmitter switching in the PFC. The 2nd specific aim will determine whether there is a causal link between neurotransmitter switching and drug- induced behavioral alterations including cognitive deficits, behavioral sensitization, and drug-induced reinforcement.