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）：由于复发的发生率很高，药物依赖性被认为是慢性疾病。人们认为，通过药物消费或暴露于药物体验中存在的刺激（例如用具或环境）产生的激励动机作用（例如，渴望）在复发中起着重要作用。尽管这些现象重要的是复发，但对所涉及的神经机制知之甚少。边缘皮层回路在最初中性刺激和奖励之间的情感，记忆和建立中发挥作用，可能参与这些影响。此外，越来越多的证据表明，多巴胺，5-羟色胺（5-HT）和谷氨酸神经递质系统也可能在这些作用中起关键作用。这项研究的目的是研究可卡因和可卡因养生环境刺激产生的激励动机作用中边缘 - 皮层电路的作用。我们假设中央和基底外侧杏仁核在可卡因和可卡因配对的刺激的激励动机中起主要作用，而前扣带和前扣带的皮层在两种刺激的刺激性影响中都起着关键的作用。我们将通过研究这些区域的兴奋性病变对可卡因条件偏好（CPP）的采集，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生成刺激的激励动机作用，而可卡因启动注射恢复了CPP的恢复原状被认为反映了可卡因本身的激励动机作用。此外，我们将调查大脑的关键区域，这些区域涉及学习，记忆力，动机和感觉运动过程，以响应可卡因培养的刺激暴露或使用直接的早期基因（IEG），C-FOS和ZIF/268的诱导可卡因剂量注射可卡因剂或可卡因启动注射。此外，我们将表征表现出IEG诱导的神经元，以确定它们是否共表达多巴胺D1，D2或D3受体，5-HT1A，5-HT2A，5-HT2A，5-HT2C和5-HT2C和5-HT4受体，以及使用谷氨酸AMPA受体glurl，glurl，Glur，Glur3和douppler3，使用doupply-hybriations intu-hybriations使用doupder-hybrID。随后，我们将通过检查破坏可卡因-CPP对与病变部位相互关联的大脑区域的IEG反应的病变的影响来建立这些研究。与病变部位相互关联的区域中IEG表达的破坏将表明可能与可卡因-CPP获取有关的区域之间的功能联系。这些实验将提供有关杏仁核和皮质大脑区域在可卡因激励动机中的作用的许多新信息，并将有助于阐明可卡因和可卡因型型刺激引起的复发的神经回路。这些发现可能对于开发可卡因依赖性的行为和药理治疗可能很有用。