Limbic-cortical involvement in drug seeking

描述(申请人提供)：药物依赖被认为是一种慢性疾病，因为复发率很高。吸食毒品或在吸毒过程中暴露于刺激物(如用具或环境)所产生的激励性动机效应(如渴望)被认为是复发的主要原因。尽管这些现象对复发很重要，但人们对其中涉及的神经机制知之甚少。边缘-大脑皮层回路在情绪、记忆以及最初中性刺激和奖励之间形成联系方面发挥作用，可能参与了这些影响。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效应中发挥关键作用。本研究的目的是考察边缘-皮质环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对刺激的激励效应中起主导作用，而前扣带回和前扣带回在这两种刺激的激励效应中起关键作用。我们将通过检测这些区域的兴奋性损伤对可卡因条件性位置偏爱(CPP)的获得、表达和可卡因恢复的影响来研究这些假说。CPP的表达被认为反映了可卡因对刺激的激励作用，而通过可卡因注射使消失的CPP恢复则被认为反映了可卡因本身的激励作用。此外，我们将调查大脑中参与学习、记忆、动机和感觉运动过程的关键区域，以c-fos和ZIF/268为标记，在暴露于与可卡因配对的刺激或可卡因注射的情况下，对神经元进行激活。此外，我们将利用双标记原位杂交技术对表现出IEG诱导的神经元进行鉴定，以确定它们是否共表达多巴胺D1、D2或D3受体、5-HT1A、5-HT2A、5-HT2C和5-HT4受体以及谷氨酸AMPA受体亚单位GluR1、GluR2和GluR3的mRNAs。随后，我们将在这些研究的基础上，检查干扰可卡因-CPP获得的病变对与病变部位相互连接的大脑区域IEG反应的影响。在与病变部位相互连接的区域中IEG表达的中断将提示可能参与获得可卡因-CPP的区域之间的功能连接。这些实验将提供许多关于杏仁核和皮质脑区在可卡因激励动机中所起作用的新信息，并将有助于阐明涉及可卡因和可卡因对刺激引起的复发的神经电路。这一发现可能有助于开发可卡因依赖的行为和药物治疗方法。

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.