Brain imaging and cognitive effects of cocaine self-administration in monkeys

描述（由申请人提供）：尽管可卡因成瘾仍然是一个主要的公共卫生问题，但目前没有有效的药物。更彻底地了解长期使用可卡因对大脑的影响以及这些变化对认知功能的影响，将有助于开发治疗可卡因依赖的方法。利用动物模型进行药物滥用研究将有助于实现这一目标。这项为期一年的拨款提案的主要目的是在猴子身上实施脑成像技术扩散张量成像（DTI）和磁共振波谱（MRS），以生成数据，以支持更广泛的未来提案。另一个目的是记录长期自我服用可卡因对猴子大脑和行为的影响。为了实现这些目标，将对8只雌性食蟹猴进行两次DTI/MRS扫描，以建立适当的测试-重测效度（具体目标1）。随后，猴子自行服用可卡因（6.0 mg/kg/天）三个月，在此期间将进行后续的DTI/MRS扫描。在此之后，四只猴子将继续自我服用可卡因，而其余四只猴子将停止接触可卡因，并将在三个月后进行最后一次DTI/MRS扫描（具体目标2）。此外，每隔一周将使用延迟匹配样本任务评估认知功能（具体目标3）。总体假设是，在可卡因自我给药和戒断期间，在白质完整性、神经代谢物浓度和认知功能方面将观察到进行性和平行的改变，这涉及长期可卡因使用后观察到的认知衰退的特定大脑区域和病理生理机制。因此，除了提供数据，以支持建立私家侦探本研究的结果将大大提高我们对慢性可卡因使用的影响的理解，对人类可卡因滥用者的成像研究的解释，药物开发，并最终对可卡因依赖的治疗。

DESCRIPTION (provided by applicant): Although cocaine addiction persists as a major public health concern, effective medications are currently unavailable. Development of treatments for cocaine dependence will be aided by a more thorough understanding of the effects of long-term cocaine use on the brain and the impact of these changes on cognitive function. Studies using animal models with proven validity in drug abuse research will help achieve this goal. The primary aim of this 1-year grant proposal is to implement the brain imaging techniques diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) in monkeys to generate data to support more extensive future proposals. Additional aims are to document the effects of chronic cocaine self- administration on the brain and behavior in monkeys. To accomplish these aims, a DTI/MRS scan will be performed twice on eight female cynomolgus monkeys to establish appropriate test-retest validity (Specific Aim 1). Subsequently, monkeys will self-administer cocaine (6.0 mg/kg/day) for three months, at which time a follow-up DTI/MRS scan will be conducted. After this point, four monkeys will continue to self-administer cocaine while cocaine exposure is discontinued in the remaining four, and a final DTI/MRS scan will be conducted three months later (Specific Aim 2). In addition, cognitive function will be assessed every other week using a delayed match-to-sample task (Specific Aim 3). The overarching hypothesis is that progressive and parallel alterations will be observed in white matter integrity, neurometabolite concentrations and cognitive function during cocaine self-administration and abstinence that implicate specific brain regions and pathophysiological mechanisms in the cognitive decline observed after long-term cocaine use. Thus, in addition to providing data to support the establishment of the P.I.'s independent research career, results of the present studies will considerably enhance our understanding of the effects of chronic cocaine use, interpretation of imaging studies in human cocaine abusers, medications development, and, ultimately, treatment of cocaine dependence.