Amphetamine Sensitization and Prefrontal Cortex Function

描述（由申请人提供）： 反复接触精神兴奋剂药物，如安非他明（AMPH），往往会导致行为敏化，这是指增强运动反应，随后的药物管理。大脑解剖结构和功能的改变与行为变化平行，这些适应性改变被假设有助于人类药物成瘾的发展和维持。大量的研究，主要是在大鼠中进行的，涉及多巴胺和谷氨酸含有皮质边缘和纹状体通路内的脑区作为重要的解剖基板AMPH诱导的行为敏化。特别是，内侧前额叶皮层（mPFC）似乎发挥了重要的作用，通过其影响腹侧被盖区和延髓核，分别在行为敏化的诱导和表达。因此，清醒的，行为主体的mPFC功能的研究是必要的，以验证药物诱导的可塑性的mPFC是重要的行为敏化，如果神经元反应的变化与其诱导和/或表达。在这里提出的实验中，我们将测试以下假设：（1）AMPH对mPFC神经元具有急性效应，这取决于神经元在行为和/或特定环境背景下的反应性，以及（2）对AMPH重复间歇给药的行为致敏与mPFC神经元的放电率和/或模式的变化相关，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记录大鼠mPFC中的单神经元活动，这些大鼠被允许在开放场竞技场中不受限制地运动。记录将在基线条件下、生理盐水给药后和大鼠接受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，并将进一步加深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.