Amphetamine Sensitization and Prefrontal Cortex Function

描述(由申请人提供)： 反复接触安非他明(Amph)等精神刺激性药物往往会导致行为敏化，这指的是对随后给药的运动反应增强。大脑解剖和功能的变化与行为变化平行，这些适应被假设为有助于人类药物成瘾的发展和维持。大量研究表明，皮质-边缘和纹状体通路中含有多巴胺和谷氨酸的脑区是AMPH诱导行为敏化的重要解剖底物，这些研究大多在大鼠身上进行。特别是，内侧前额叶皮质(MPFC)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重要作用。因此，有必要对清醒、行为受试者的mPFC功能进行研究，以验证药物诱导的mPFC可塑性是否对行为敏化很重要，以及神经元反应的变化是否与其诱导和/或表达相关。在这里提出的实验中，我们将检验以下假设：(1)AMPH对mPFC神经元具有急性影响，依赖于神经元在行为过程中和/或对特定环境背景的反应，(2)对重复、间歇给药的行为敏化与mPFC神经元的放电频率和/或模式的变化相关，这种关系在非敏化动物中将有所不同。我们将使用长期植入的多丝电极来记录允许在开阔场地自由活动的大鼠mPFC中的单个神经元活动。记录将在基线条件下、注射生理盐水后以及大鼠接受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，并将进一步了解与重复药物摄入相关的神经适应。

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.