Limbic-cortical involvement in drug seeking

边缘皮质参与药物寻求

• 批准号: 6542474
• 负责人: Janet L Neisewander
• 金额: $ 33.74万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-12 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6542474
• 关键词: amygdala; behavioral /social science research tag; cingulate gyrus; cocaine; craving; drug abuse; excitatory aminoacid; in situ hybridization; laboratory rat; learning; limbic system; memory; motivation; neuroanatomy; neurotransmitters; preference; regulatory gene; sensorimotor system; substance abuse related behavior

DESCRIPTION (provided by applicant): Drug dependence is considered a chronic disease due to the high incidence of relapse. Incentive motivational effects (e.g., craving) produced by consumption of drug or by exposure to stimuli present during the drug experience (e.g., paraphernalia or the environment) are thought to play a major role in relapse. Despite the importance of these phenomena to relapse, little is known about the neural mechanisms involved. Limbic-cortical circuits, which play a role in emotion, memory, and formation of associations between initially neutral stimuli and rewards, are likely involved in these effects. Furthermore, mounting evidence suggests that dopamine, serotonin (5-HT), and glutamate neurotransmitter systems may play a critical role in these effects as well. The objective of this research is to examine the role of limbic-cortical circuits in the incentive motivational effects produced by cocaine and cocaine-paired environmental stimuli. We hypothesize that the central and basolateral amygdala play predominant roles in the incentive motivational effects of cocaine and cocaine-paired stimuli, respectively, whereas the prelimbic and anterior cingulate cortex play a critical role in the incentive motivational effects of both types of stimuli. We will investigate these hypotheses by examining the effects of excitotoxic lesions of these regions on acquisition, expression, and cocaine reinstatement of cocaine-conditioned place preference (CPP). Expression of CPP is thought to reflect incentive motivational effects of cocaine-paired stimuli, whereas reinstatement of extinguished CPP by cocaine priming injections is thought to reflect the incentive motivational effects of cocaine itself. In addition, we will survey key regions of the brain that are involved in learning, memory, motivation, and sensorimotor processes for neuronal activation in response to exposure to cocaine-paired stimuli or to cocaine priming injections using induction of immediate early genes (IEGs), c-fos and zif/268, as markers. Furthermore, we will characterize the neurons that exhibit IEG induction to determine whether they co-express mRNAs for dopamine D1, D2, or D3 receptors, 5-HT1A, 5-HT2A, 5-HT2C, and 5-HT4 receptors, and glutamate AMPA receptor subunits GluRl, GluR2, and GluR3 using double-labeling in situ hybridization. Subsequently, we will build from these studies by examining the effects of lesions that disrupt acquisition of cocaine-CPP on IEG responses in brain regions interconnected with the lesion site. A disruption of IEG expression in regions interconnected with the lesion site would suggest functional connection between the regions that may be involved in acquisition of cocaine-CPP. These experiments will provide much new information on the role of the amygdala and cortical brain regions in incentive motivation for cocaine and will help elucidate the neural circuitry involved in relapse elicited by cocaine and cocaine-paired stimuli. The findings may be useful for developing behavioral and pharmacological treatments for cocaine dependence.

描述（由申请人提供）：药物依赖被认为是一种慢性疾病，因为复发率高。由吸毒或在吸毒过程中暴露于刺激物（如随身物品或环境）所产生的激励效应（如渴望）被认为在复发中起主要作用。尽管这些现象对复发很重要，但对其中的神经机制知之甚少。大脑边缘皮层回路在情绪、记忆以及最初的中性刺激和奖励之间的关联形成中发挥作用，可能与这些效应有关。此外，越来越多的证据表明，多巴胺、血清素（5-HT）和谷氨酸神经递质系统也可能在这些影响中发挥关键作用。本研究的目的是探讨边缘-皮层回路在可卡因和可卡因配对环境刺激产生的激励动机效应中的作用。我们假设中央杏仁核和基底外侧杏仁核分别在可卡因和可卡因配对刺激的激励动机效应中起主导作用，而前边缘皮层和前扣带皮层在这两种刺激的激励动机效应中起关键作用。我们将通过检查这些区域的兴奋毒性病变对可卡因条件位置偏好（CPP）的获得、表达和可卡因恢复的影响来研究这些假设。CPP的表达被认为反映了可卡因配对刺激的激励动机效应，而通过可卡因启动注射恢复已消失的CPP被认为反映了可卡因本身的激励动机效应。此外，我们将使用直接早期基因（IEGs）， c-fos和zif/268作为标记，研究暴露于可卡因配对刺激或可卡因启动注射时，涉及学习、记忆、动机和感觉运动过程的大脑关键区域的神经元激活。此外，我们将对表现出IEG诱导的神经元进行表征，以确定它们是否共同表达多巴胺D1、D2或D3受体、5-HT1A、5-HT2A、5-HT2C和5-HT4受体以及谷氨酸AMPA受体亚基GluRl、GluR2和GluR3的mrna。随后，我们将在这些研究的基础上，检查破坏可卡因- cpp获取的病变对与病变部位相连的大脑区域的IEG反应的影响。在与病变部位相连的区域中，IEG表达的中断表明，可能涉及可卡因- cpp获得的区域之间存在功能联系。这些实验将为杏仁核和大脑皮层区域在可卡因刺激动机中的作用提供许多新的信息，并将有助于阐明可卡因和可卡因配对刺激引起的复发所涉及的神经回路。这一发现可能有助于开发针对可卡因依赖的行为和药物治疗方法。