Central HIV-1 Tat exposure elevates anxiety and fear conditioned responses of male mice concurrent with altered mu-opioid receptor-mediated G-protein activation and β-arrestin 2 activity in the forebrain.
Central HIV-1 Tat exposure elevates anxiety and fear conditioned responses of male mice concurrent with altered mu-opioid receptor-mediated G-protein activation and β-arrestin 2 activity in the forebrain.
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DOI：
10.1016/j.nbd.2016.01.014
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发表时间：
2016-08
影响因子：
6.1
通讯作者：
Knapp PE
中科院分区：
文献类型：
--
作者：
Hahn YK;Paris JJ;Lichtman AH;Hauser KF;Sim-Selley LJ;Selley DE;Knapp PE
共同暴露于阿片类药物和HIV/HIV蛋白导致HIV+个体和动物模型中CNS形态和行为缺陷增强。具有滥用倾向的阿片类药物，如海洛因和吗啡，优先与μ阿片受体（MORs）结合并通过MORs发挥药理作用。阿片类药物与艾滋病毒相互作用的机制尚不清楚。暴露于HIV-1转录反式激活因子（达特）蛋白导致与人类疾病的许多方面相似的神经退行性结果。我们还观察到体内暴露于达特导致吗啡功效的明显变化，因此假设HIV蛋白可能改变莫尔活化。为了验证我们的假设，MOR介导的G蛋白激活确定在神经艾滋病相关的前脑区域的转基因小鼠诱导中枢神经系统表达的HIV-1达特。通过脑切片中莫尔激动剂刺激的[35 S]鸟苷-5 ′-O-（3-硫代）三磷酸（[35 S]GTPγS）放射自显影，以及从特定脑区域分离的膜中莫尔激动剂刺激的[35 S]GTPγS结合的浓度-效应曲线，评估G蛋白活化。使用MOR选择性激动剂DAMGO（[D-Ala 2，N-MePhe 4，Gly-ol]-脑啡肽）和更临床相关的激动剂吗啡进行比较研究。达特暴露以激动剂、时间和区域依赖性方式降低MOR介导的G蛋白活化。发现参与莫尔脱敏的GPCR调节蛋白β-arrestin-2的水平仅在一个受影响的大脑区域（杏仁核）中升高;通过免疫共沉淀，杏仁核β-arrestin-2也显示出与莫尔的显著增加的关联，表明莫尔的可用性降低。有趣的是，这与焦虑和恐惧条件性消退的变化有关，这些行为有大量的杏仁核输入。我们认为HIV-1达特改变了莫尔响应激动剂结合的内在信号能力，可能是通过涉及β-抑制蛋白-2的表达和/或功能改变的机制。
Co-exposure to opiates and HIV/HIV proteins results in enhanced CNS morphological and behavioral deficits in HIV+ individuals and in animal models. Opiates with abuse liability, such as heroin and morphine, bind preferentially to and have pharmacological actions through μ-opioid-receptors (MORs). The mechanisms underlying opiate-HIV interactions are not understood. Exposure to the HIV-1 transactivator of transcription (Tat) protein causes neurodegenerative outcomes that parallel many aspects of the human disease. We have also observed that in vivo exposure to Tat results in apparent changes in morphine efficacy, and thus have hypothesized that HIV proteins might alter MOR activation. To test our hypothesis, MOR-mediated G-protein activation was determined in neuroAIDS-relevant forebrain regions of transgenic mice with inducible CNS expression of HIV-1 Tat. G-protein activation was assessed by MOR agonist-stimulated [35S]guanosine-5′-O-(3-thio)triphosphate ([35S]GTPγS) autoradiography in brain sections, and in concentration-effect curves of MOR agonist-stimulated [35S]GTPγS binding in membranes isolated from specific brain regions. Comparative studies were done using the MOR-selective agonist DAMGO ([D-Ala2, N-MePhe4, Gly-ol]-enkephalin) and a more clinically relevant agonist, morphine. Tat exposure reduced MOR-mediated G-protein activation in an agonist, time, and regionally dependent manner. Levels of the GPCR regulatory protein β-arrestin-2, which is involved in MOR desensitization, were found to be elevated in only one affected brain region, the amygdala; amygdalar β-arrestin-2 also showed a significantly increased association with MOR by co-immunoprecipitation, suggesting decreased availability of MOR. Interestingly, this correlated with changes in anxiety and fear-conditioned extinction, behaviors that have substantial amygdalar input. We propose that HIV-1 Tat alters the intrinsic capacity of MOR to signal in response to agonist binding, possibly via a mechanism involving altered expression and/or function of β-arrestin-2.