Reinforcing Efficacy of Cocaine in Genetically Variable

这项R21赠款旨在建立小鼠静脉注射可卡因的自我给药，目的是开发一个研究计划，以调查与功能神经免疫相互作用对可卡因增强疗效和戒除后复发自我给药的作用有关的更广泛的问题。基因工程的进步使得能够实验性地修改小鼠基因组的离散成分，使研究特定基因和/或基因组合如何影响行为和生物功能成为可能。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。CD81分子是一种免疫相关分子，除了由B淋巴细胞表达外，还在大脑中发现，在给大鼠非或有可卡因后表达CD81。初步数据显示，与C57BL/6野生型对照相比，CD81基因敲除小鼠中可卡因的增强效果可能不那么明显。具体目标1我们将在C57BL/6小鼠中建立IV自我给药，使用鼻戳作为操作性反应，并检查紧随操作性反应的音调的次级强化属性。将使用不同单位剂量的可卡因来确定获取、维护和熄灭参数。第二个实验将在CD81基因敲除小鼠中进行，看看在这些阶段的反应率是否与野生型小鼠对照的不同。根据非偶然注射可卡因改变免疫功能的证据，特定目标2将确定自身注射不同单位剂量(0.1-1 mg/kg)的可卡因是否改变体内细胞因子(白介素1[IL-1]、白介素2、肿瘤坏死因子和干扰素-伽马)对细菌“超级抗原”葡萄球菌肠毒素A(SEA)的反应。CD81基因敲除和野生型对照动物都将被检查。最后，在特定的目标3中，将根据(I)条件性位置偏爱和(Ii)静脉自我给药范例中测试的致炎细胞因子(小鼠IL-1β)的作用，根据其引起药物寻找行为复发的能力来研究其作用。通过与足底电击的比较，将确定系统性应激源和过程性应激源在导致小鼠复发的能力上是否存在差异。还将通过检测CRH和c-fos mRNA以及血浆皮质酮和ACTH水平来检验预先接触可卡因对IL-1β的神经生物学反应的影响。这些研究的结果将特别新颖，因为它们可能在参与神经免疫相互作用的成分的药物成瘾和戒断过程中发挥重要的调节作用。这是直接相关的，因为药物滥用(包括可卡因)与高度传染病(特别是。艾滋病毒)。

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).