Amphetamine Sensitization and Prefrontal Cortex Function

描述（由申请人提供）： 反复接触安非他明 (AMPH) 等精神兴奋药物通常会导致行为过敏，即对后续药物给药的运动反应性增强。大脑解剖结构和功能的改变与行为变化平行，并且这些适应被假设有助于人类毒瘾的发展和维持。大量研究（主要在大鼠中进行）表明，皮质边缘和纹状体通路中含有多巴胺和谷氨酸的大脑区域是 AMPH 诱导的行为敏化的重要解剖基质。特别是，内侧前额叶皮层（mPFC）似乎通过分别影响腹侧被盖区和伏隔核，在行为敏化的诱导和表达中发挥着重要作用。因此，有必要对清醒、有行为能力的受试者的 mPFC 功能进行研究，以验证药物诱导的 mPFC 可塑性对于行为敏化是否重要，以及神经元反应的变化是否与其诱导和/或表达相关。在此提出的实验中，我们将测试以下假设：（1）AMPH 对 mPFC 神经元有急性影响，这取决于神经元在行为期间和/或对特定环境背景的反应性，（2）对重复、间歇性施用 AMPH 的行为敏感度与 mPFC 神经元的放电率和/或模式的变化相关，并且这种关系在非致敏动物中会有所不同。我们将使用长期植入的多线电极来记录大鼠 mPFC 中的单神经元活动，这些大鼠被允许在开放场地中不受限制地运动。记录将在基线条件下、盐水给药后以及大鼠接受 AMPH 急性或慢性治疗后获得。最终，这些实验将有助于阐明 mPFC 可塑性在行为敏化中的作用，并将进一步我们对与重复药物摄入相关的神经适应的理解。

DESCRIPTION (provided by applicant): Repeated exposure to psychostimulant drugs such as amphetamine (AMPH) often leads to behavioral sensitization, which refers to enhanced motor responsiveness to subsequent drug administration. Alterations in brain anatomy and function parallel behavior changes and these adaptations have been hypothesized to contribute to the development and maintenance of human drug addiction. A large body of studies, mostly performed in rats, has implicated dopamine- and glutamate-containing brain areas within cortico-limbic and striatal pathways as important anatomical substrates for AMPH-induced behavioral sensitization. In particular, the medial prefrontal cortex (mPFC) appears to play an important role in the induction and expression of behavioral sensitization through its influence on the ventral tegmental area and nucleus accumbens, respectively. Thus, studies of mPFC function in awake, behaving subjects are necessary to verify if drug-induced plasticity in the mPFC is important for behavioral sensitization and if changes in neuronal responses correlate to its induction and/or expression. In the experiments proposed here, we will test the following hypotheses: (1) AMPH has acute effects on mPFC neurons that depend on the neuron's responsiveness during behavior and/or to a particular environmental context, and (2) Behavioral sensitization to repeated, intermittent administration of AMPH is correlated with changes in the firing rate and/or pattern of mPFC neurons and this relationship will differ in non-sensitized animals. We will use chronically implanted, multiwire electrodes to record single-neuron activity in the mPFC of rats that are allowed unrestricted movement in an open-field arena. Recordings will be obtained during baseline conditions, after saline administration, and after rats have undergone either acute or chronic treatment with AMPH. Ultimately, these experiments will help clarify the role of mPFC plasticity in behavioral sensitization and will further our understanding of the neuroadaptations associated with repeated drug intake.