NEUROBIOLOGY OF COCAINE ABUSE DETECTED BY FUNCTIONAL MRI

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。1)将药物刺激的中性性质转变为人脑药物奖励预测因子的神经关联。17名人类可卡因吸食者和18名对照者通过功能磁共振成像（fMRI）方法成功地参与了可卡因线索诱导的可卡因渴望研究。内容特异性和群体特异性表明，可卡因线索电影成功地诱发了主观渴望，并激活了两组成瘾编码的神经相关细胞。一组与心理唤醒、情景记忆检索、注意力和前额叶（如布罗德曼10区）、颞叶和枕叶皮层的行为计划有关。另一组与可卡因渴望等级呈正相关，如在胶质下皮层（SCC）和前内侧眶额皮层（amOFC）。我们的研究结果表明，SCC中的神经相关因子已经将环境药物刺激从中性性质转变为可卡因奖励的预测因子。导致这种转变的神经生物学机制可能是由于过度学习线索-药物配对（成瘾的一个关键神经生物学特征），SCC完成了从非条件奖励探测器到条件奖励预测器的功能建立。提示amOFC区域的激活信号代表了动机电位，而渴望是这种驱动药物寻找和服用行为的动机电位的表现。2) fMRI检测急性可卡因给药对人脑的神经反应。理解导致吸毒行为改变的神经生物学过程是成瘾研究的核心挑战。利用改进的功能性磁共振成像（fMRI）方法检测血氧水平依赖性（BOLD）对比，我们报道了急性可卡因给药对人类可卡因使用者同时激活中脑边缘和中脑皮层多巴胺能投射，这反过来可能开启了介导联想学习、动机和记忆的前前额叶皮质（aPFC）、Brodmann区10 （BA10）和眶额皮质（OFC）的分层脑网络。结果表明，中皮质边缘多巴胺能回路的负向BOLD信号代表了药物诱导成瘾行为习得所必需的自下而上的奖励编码过程，而BA10和OFC区域的正向BOLD信号代表了反复使用可卡因可以反复启动的自下而上的成瘾编码过程，从而加强这种习得性关联，使其进入成瘾状态。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 1) The Neural Correlates for Shifting the neutral Nature of Drug Stimuli to be the Predictors of Drug Rewards in the Human Brain. Seventeen human cocaine users and eighteen control human subjects successfully participated in the cocaine-cue elicited cocaine craving study by using functional MRI (fMRI) method. The content-specificity and population specificity indicated that cocaine-cue films successfully elicited subjective craving and activated two groups of the addiction-encoded neural correlates. One group is associated with the psychological arousal, episodic memory retrieval, attention, and behavioral planning in the prefrontal (such as in Brodmann Area 10), temporal and occipital cortex. The other group is positively correlated with the cocaine craving rating, such as in the subcollosal cortex (SCC) and the anterior medial orbitofrontal cortex (amOFC). Our results demonstrate that the neural correlates in the SCC have shifted the environmental drug stimuli from their neutral nature to the predictors of cocaine rewards. The neurobiological mechanisms responsible for such a shift may be the completion of a functional establishment in SCC from an unconditioned reward detector to conditioned reward predictor due to the over-learning of the cue-drug pairing, a key neurobiological characteristic of the addiction. It is suggested that the activated signal in the amOFC region represent the motivational potential and the craving is the manifestation of this motivational potential that drives the drug seeking and taking behavior. 2) Neural Responses to Acute Cocaine Administration in the Human Brain Detected by fMRI. Understanding the neurobiological processes responsible for the altered behaviors that drives drug-taking behavior is a central challenge in addiction research. With an improved functional MRI (fMRI) method for detecting a blood oxygenation level dependent (BOLD) contrast, we report that acute cocaine administration to human cocaine users concurrently activates the mesolimbic and mesocortical dopaminergic projections, which in turn may gate the hierarchical brain networks in anterior prefrontal cortex (aPFC) of the Brodmann Area 10 (BA10) and orbitofrontal cortex (OFC) that mediate associative learning, motivation and memory. It is suggested that the negative BOLD responses in the mesocorticolimbic dopaminergic circuitry represent the bottom-up reward encoding processes essential for drug-induced acquisition of addictive behavior, whereas the positive BOLD signal in the BA10 and OFC regions represents the bottom-up addiction encoding processes that repeated cocaine use could repeatedly initiate to strengthen this learned association into a state of addiction.