NEUROBIOLOGY OF COCAINE WITHDRAWAL AND SOCIAL STRESS

描述：(申请人摘要) 该项目的长期目标是确定 应激诱导的改变和敏化的神经适应事件 可卡因在大鼠前脑环路中的自我给药。一个 综合行为、神经化学和分子方法将用于 阐明压力暴露的影响背后的调节变化 关于可卡因致敏的。该项目的具体目标是：(1) 描述行为的时间进程和细胞基础 可卡因自身给药对皮质纹状体的敏化作用 电路，(2)检查显著的社会应激源对 核内多巴胺和谷氨酸能对可卡因攻击的反应 可卡因戒断时的伏隔神经(NAC)，(3)测定神经 急性或慢性社会应激可增强对 可卡因激发，以及(4)评估谷氨酸能输入对 应激诱导的可卡因反应的改变 谷氨酸受体mRNA的表达及NMDA作用的评价 慢性社会应激时受体阻断对A反应的影响 随后的可卡因挑战。大鼠将被植入静脉注射 导尿管，然后暴露在慢性社会压力或可卡因中 自我给药后停药0、3或21天。蜂窝 对急性静脉注射可卡因激发的反应 应激将在中皮质边缘和其他神经元中使用原位检测 寡脱氧核苷酸探针的杂交组织化学 与编码c-fos以检测细胞激活的序列互补， 它将与从同一计算机上获得的运动活动数据相关 动物。体内微透析将被用来检测细胞外水平 多巴胺、谷氨酸和可卡因及其代谢物 挑战。慢性应激或可卡因暴露对谷氨酸的影响 将使用ISHH检查受体以评估NMDA和AMPA受体 以区分和本地化选择性的区域效应。一起， 这些研究将检查神经回路中的功能联系 在可卡因戒断过程中的压力和敏化，这可能导致 对可卡因的渴求和对可卡因自我管理的复发。结果是 将阐明强化和应激刺激背后的机制(S) 以及细胞和分子的变化在 可卡因戒断。这一优势将使设计变得更好 治疗可卡因依赖的方法。

DESCRIPTION: (Applicant's Abstract) The long-term objectives of the project are to characterize the neuroadaptive events underlying stress-induced alteration and sensitization following cocaine self-administration in forebrain circuits of the rat. An integrated behavioral, neurochemical and molecular approach will be used to elucidate the regulatory changes underlying the effects of stress exposure on cocaine sensitization. The specific aims of the project are: (1) to characterize the time course and the cellular basis of behavioral sensitization induced by cocaine self-administration in corticostriatal circuits, (2) to examine the impact of a salient social stressor on dopaminergic and glutamatergic response to cocaine challenge in the nucleus accumbens (NAc) during cocaine withdrawal, (3) to determine the neural circuits by which acute or chronic social stress can enhance the response to cocaine challenge, and (4) to assess the influence of glutamatergic input on stress induced alteration of cocaine response by examining changes in the expression of glutamate receptor mRNA and by assessing the effect of NMDA receptor blockade during chronic social stress exposure on the response to a subsequent cocaine challenge. Rats will be implanted with intravenous catheters, then exposed to chronic social stress or cocaine self-administration followed by 0, 3 or 21 days of withdrawal. Cellular response to acute intravenous cocaine challenge with or without prior acute stress will be examined in mesocorticolimbic and other neurons using in situ hybridization histochemistry (ISHH) with oligodeoxynucleotide probes complementary to the sequence encoding c-fos to detect cellular activation, which will be correlated with motor activity data obtained from the same animals. In vivo microdialysis will be used to examine extracellular levels of dopamine, glutamate and cocaine, and their metabolites following cocaine challenge. The influence of chronic stress or cocaine exposure on glutamate receptors will be examined using ISHH to assess NMDA and AMPA receptors in order to differentiate and localize selective regional effects. Together, these studies will examine the functional link in neural circuits between stress and sensitization during cocaine withdrawal, which could result in cocaine craving and relapse to cocaine self-administration. The results will elucidate the mechanism(s) underlying reinforcing and stressful stimuli as well as the cellular and molecular alterations which develop during cocaine withdrawal. This know]edge will permit the design of better approaches to treat cocaine dependence.