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

项目摘要摘要： 反复接触滥用药物会导致成瘾、慢性和复发性 疾病被定义为寻求和服用药物的强迫症，限制摄入的失控， 以及消极情绪状态的出现。从吸毒到上瘾的转变包括 大脑回路的神经可塑性与奖赏、冲动控制和情感有关。大脑中的一个区域是 因药物摄入而功能受损的是前额叶皮质(PFC)，在那里，滥用药物会导致大脑 似乎与失去对药物摄取的控制有关的活动。增加我们对 滥用药物影响这些回路的方式对于更好地理解机制是很重要的。 为向成瘾过渡奠定基础，并允许开发新的干预和治疗方法。 大脑回路的正常功能依赖于神经传递的正确规范和协调。 越来越多的证据最近证实，当长期的环境刺激产生 神经元亚群的电活动的持续改变，这些神经元可以经历 它们所表达的神经递质的重新指定，通常导致从兴奋性到兴奋性的转换 抑制性递质或反之亦然。这种新认识的神经可塑性形式，称为神经递质 切换，在成年哺乳动物的大脑中被反复观察到，并与 动物的行为。 我们假设，反复接触滥用药物可以诱导神经递质的转换，进而 有助于建立药物诱导的行为改变，如认知障碍、行为 敏化和药物诱导的强化。有两个具体目标将检验这一假设。第一个具体目标 将测试PCP或冰毒的亚慢性治疗是否会诱导PFC中的神经递质转换。这个 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联系- 诱发的行为改变，包括认知缺陷、行为敏感化和药物诱导 增援。

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.