fMRI of cue-reactivity and impulsivity in recreational vs dependent cocaine users

描述（由申请人提供）：可卡因依赖在美国是一个主要的公共卫生问题，目前没有FDA批准的治疗方法。最近的动物研究表明，长期使用可卡因会改变与动机和奖励有关的大脑回路，并确定了几个新的治疗干预目标。然而，这项研究的大多数发现尚未在人类中进行评估。功能神经成像技术提供了独特的机会来检查动物研究结果对人类的普遍性。然而，尽管大多数功能性神经成像研究都集中在可卡因依赖者和可卡因幼稚者之间的比较，但最近的成瘾动物模型强调了检查自愿（或“娱乐”）和强迫（或“依赖”）可卡因使用者在对可卡因线索的神经反应方面的差异的重要性。后一种比较是至关重要的，因为，与可卡因新手不同的是，可卡因刺激对娱乐使用者的动机是显著的，并且有望激活与奖励有关的大脑中心。总而言之，识别可卡因依赖者和娱乐性可卡因使用者对可卡因线索的大脑激活的差异，可能为人类从自愿到强迫性可卡因使用的转变提供重要的见解。在这项研究的目的1中，30名依赖可卡因和30名娱乐性可卡因使用者将参加一个功能磁共振成像（fMRI）实验，其中包括可卡因线索暴露任务，他们将被要求观看中性和可卡因相关的图片。根据动物研究的结果，我们假设可卡因依赖者在暴露于可卡因线索时，与娱乐使用者相比，其背纹状体活动明显增加，腹侧纹状体和额叶活动明显减少。最近对啮齿动物的研究也证实，与非冲动的老鼠相比，在接触可卡因之前冲动较大的老鼠更有可能发展成强迫性的可卡因使用模式。人类神经影像学研究表明，当要求可卡因依赖个体抑制阳性反应时，与可卡因未接触的个体相比，涉及行为约束（例如，前扣带）的大脑额叶区域的激活较少。然而，没有研究比较依赖性和娱乐性可卡因使用者在反应抑制相关的额叶脑激活方面的差异。因此，为了研究拟议研究的目的2，上述依赖性和娱乐性可卡因使用者将完成反应抑制（即go no-go）功能磁共振成像任务。我们假设，与娱乐性可卡因使用者相比，当被要求抑制强性反应时，依赖可卡因使用者会表现出明显更少的前扣带和其他额叶脑活动。拟议研究的结果将有助于扩展最近关于人类可卡因成瘾相关的神经回路变化的动物研究，并在这样做时，将为开发新的治疗药物提供支持。重要的是，拟议的研究与NIDA的使命是一致的，“将科学的力量应用于药物滥用和成瘾”，特别是与NIDA的预防目标是一致的，“提高和扩大我们对基础神经生物学的理解，因为它与药物滥用和成瘾背后的大脑回路有关。”

DESCRIPTION (provided by applicant): Cocaine dependence is a major public health concern in the United States with no currently FDA approved treatments. Recent animal research has demonstrated that chronic cocaine use alters brain circuitry involved with motivation and reward, and has identified several novel targets for therapeutic intervention. However, most of the findings from this research have not been evaluated in humans. Functional neuroimaging techniques provide unique opportunities to examine the generalizability of animal research findings to humans. However, whereas most functional neuroimaging studies have focused on comparisons between cocaine dependent and cocaine-naive individuals, recent animal models of addiction have emphasized the importance of examining differences between voluntary (or "recreational") and compulsive (or "dependent") cocaine users in terms of their neural responses to cocaine cues. The latter comparison is critically important because, unlike for cocaine-naive individuals, cocaine stimuli are motivationally salient for recreational users and are expected to activate centers of the brain involved in reward. In sum, identifying differences in brain activation to cocaine cues between dependent and recreational cocaine users could potentially provide important insight into the transition from voluntary to compulsive cocaine use in humans. In Aim 1 of the proposed study, 30 dependent and 30 recreational cocaine users will participate in a functional Magnetic Resonance Imaging (fMRI) experiment including a cocaine cue exposure task, where they will be asked to view neutral and cocaine- related pictures. In accordance with findings from animal research, we hypothesize that dependent cocaine users will have significantly greater dorsal striatal and significantly less ventral striatal and frontal activity, when exposed to cocaine cues, as compared to recreational users. Recent rodent research has also established that rats characterized by greater impulsivity prior to cocaine exposure are far more likely to develop compulsive patterns of cocaine use relative to non-impulsive rats. Human neuroimaging research has demonstrated that cocaine-dependent individuals experience less activation of frontal brain regions involved in behavioral constraint (e.g., anterior cingulate) when asked to inhibit a prepotent response as compared to cocaine-naive individuals. However, no studies have compared dependent and recreational cocaine users in terms of their frontal brain activation associated with response inhibition. Thus, to investigate Aim 2 of the proposed study, the above dependent and recreational cocaine users will complete a response inhibition (i.e., go no-go) fMRI task. We hypothesize that dependent cocaine users will demonstrate significantly less anterior cingulate and other frontal brain activity, when asked to inhibit a prepotent response, as compared to recreational cocaine users. Findings from the proposed study will help to extend recent animal research regarding changes in neurocircuitry associated with cocaine addiction to humans, and in doing so, will provide support for the development of novel therapeutic agents. Importantly, the proposed study is consistent with NIDA's mission, "to bring the power of science to bear on drug abuse and addiction," and especially with NIDA's prevention objective, "to improve and expand our understanding of basic neurobiology as it relates to the brain circuitry underlying drug abuse and addiction." PUBLIC HEALTH RELEVANCE: Recent animal research has demonstrated that cocaine addiction is associated with a number of pathological changes in the brain's motivational and reward circuitry. Although these findings may offer great promise in identifying novel targets for therapeutic interventions for cocaine addiction, more research is needed to determine how well these animal research findings apply to humans. To this end, the proposed study will examine differences in brain activation to cocaine cues and response inhibition (a facet of impulsivity that is found to predict the development of cocaine addiction) between recreational (or "voluntary") and dependent (or "compulsive") cocaine users using functional Magnetic Resonance Imaging.