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

描述(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，但目前还没有有效的药物。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。在药物滥用研究中使用被证明有效的动物模型的研究将有助于实现这一目标。这项为期一年的拨款计划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)，以产生数据来支持更广泛的未来计划。其他目的是记录慢性可卡因自我给药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，以建立适当的重测效度(特定目标1)。随后，猴子将自我注射可卡因(6.0毫克/公斤/天)持续三个月，届时将进行后续的DTI/MRS扫描。在这一点之后，四只猴子将继续自我注射可卡因，而其余四只猴子将停止接触可卡因，三个月后将进行最终的DTI/MRS扫描(特定目标2)。此外，认知功能将每隔一周使用延迟的匹配样本任务(具体目标3)进行评估。最重要的假设是，在可卡因自我给药和戒断期间，白质完整性、神经代谢物浓度和认知功能将发生渐进性和平行的变化，这涉及到长期使用可卡因后观察到的认知功能下降的特定脑区和病理生理机制。因此，除了为支持P.I.S独立研究生涯的建立提供数据外，本研究的结果还将极大地提高我们对长期使用可卡因的影响、对人类可卡因滥用者的影像研究的解释、药物开发以及最终治疗可卡因依赖的理解。

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.