Reinforcing Efficacy of Cocaine in Genetically Variable

这项R21资助旨在建立小鼠静脉自我注射可卡因，目的是开发一项研究计划，以调查与功能性神经免疫相互作用有关的更广泛的问题，这些问题可以对可卡因的增强功效和在灭绝后自我注射可卡因的复发发挥作用。基因工程的进步已经导致实验性修改小鼠基因组的离散组分的能力，允许研究特定基因和/或基因组合如何影响行为和生物功能。这使得老鼠成为检查滥用药物的强化特性的宝贵工具，从而有助于治疗和预防药物成瘾。分子CD 81是一种免疫相关分子，除了由B淋巴细胞表达外，还在脑中发现，在非偶然给予大鼠可卡因后表达。初步数据显示，与C57 BL/6野生型对照相比，可卡因的增强功效在CD 81敲除小鼠中可能不太明显。具体目标1我们将在C57 BL/6小鼠中建立IV自我给药，使用鼻子戳作为操作性反应，并检查操作性反应后音调的二次强化特性。将使用不同单位剂量的可卡因确定获得、维持和消退参数。第二个实验将在CD 81敲除小鼠中进行，以观察这些阶段的应答率是否与野生型同窝对照不同。基于非偶然性可卡因注射改变免疫功能的证据，特异性目标2将确定不同单位剂量（0.1-1 mg/Kg）的可卡因自我给药是否会改变对细菌“超抗原”葡萄球菌肠毒素A（SEA）的体内细胞因子应答（白细胞介素-1 [IL-1]、IL-2、肿瘤坏死因子和干扰素-γ）。将检查CD 81敲除和野生型对照动物。最后，在具体目标3中，将研究促炎细胞因子（鼠IL-1 β）（已知可激活大脑中的应激回路）在（i）条件性位置偏好和（ii）静脉内自我给药模式中检测的导致药物寻求行为复发的能力方面的作用。与足电击的比较将确定系统性和进行性应激源在引起小鼠复发的能力方面是否不同。可卡因预暴露对IL-1 β的神经生物学反应性的影响也将通过测量CRH和c-fos mRNA以及皮质酮和ACTH的血浆水平来检查。这些研究的结果将是特别新颖的，因为它们可能会建立一个重要的调节作用，在药物成瘾和戒断的成分参与神经免疫相互作用。鉴于药物滥用（包括可卡因）与传染病（特别是艾滋病毒）的高发率有关，这一点具有直接的相关性。

This R21 grant is designed to establish intravenous self-administration of cocaine in the mouse, with the purpose of developing a research program to investigate broader issues relating to the role functional neural-immune interactions can exert on the reinforcing efficacy of cocaine and relapse to self-administer cocaine following extinction. Advances in genetic engineering have resulted in the ability to experimentally modify discrete components of the mouse genome, allowing the study of how specific genes and/or combinations of genes influence behavioral and biological functions. This has rendered the mouse an invaluable tool for examining the reinforcing properties of drugs of abuse, and thereby aiding efforts to treat and prevent drug addiction. The molecule CD81 is an immune-related molecule, which in addition to being expressed by B lymphocytes, is also found in the brain, where it is expressed following noncontingent cocaine administration to the rat. Preliminary data has shown that the reinforcing efficacy of cocaine may be less pronounced in CD81 knockout mice, when compared to their C57BL/6 wildtype controls. Specific Aim 1 we will establish IV self-administration in the C57BL/6 mouse, using nose-poke as an operant response, and examine the secondary reinforcing properties of a tone that follows the operant response. Acquisition, maintenance and extinction parameters will be determined using different unit doses of cocaine. A second experiment will pursue this in the CD81 knockout mouse to see if rate of responding during these stages varies from the wildtype littermate controls. Based on evidence that noncontingent cocaine injections alter immune function, Specific Aim 2 will determine whether self- administration of cocaine at various unit doses (0.1-1 mg/Kg) alters the in vivo cytokine response (interleukin-1 [IL-1], IL-2, tumor necrosis factor, and interferon-gamma) to a bacterial "superantigen," staphylococcal enteroxin A (SEA). Both CD81 knockout and wildtype control animals will be examined. Finally, in Specific Aim 3, the effects of a proinflammatory cytokine (murine IL-1beta), known to activate stress circuits in the brain, will be investigated in terms of its ability to cause relapse to drug-seeking behavior as tested in (i) the conditioned place preference and (ii) intravenous self-administration paradigms. A comparison with footshock will determine whether systemic and processive stressors differ in their ability to cause relapse in the mouse. The effects of cocaine preexposure on neurobiological reactivity to IL-1beta will also be examined by measuring CRH and c- fos mRNA and plasma levels of corticosterone and ACTH. The results of these studies will be especially novel in that they may establish an important modulatory role in drug addiction and withdrawal for components involved in neural-immune interactions. This is of immediate relevance, given that drug abuse (including cocaine) is associated with high levels of infectious disease (esp. HIV).