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

NEUROBIOLOGY OF DISEASE

卷:92

Article

Hahn, Yun K.¹  Paris, Jason J.²  Lichtman, Aron H.^2,3  Hauser, Kurt F.^1,2,3  Sim-Selley, Laura J.^2,3  Selley, Dana E.^2,3  Knapp, Pamela E.^1,2,3 

[1] Virginia Commonwealth Univ, Dept Anat & Neurobiol, Med Coll Virginia MCV Campus, Richmond, VA 23298 USA

[2] Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Med Coll Virginia MCV Campus, Richmond, VA 23298 USA

[3] Virginia Commonwealth Univ, Inst Drug & Alcohol Studies, Med Coll Virginia Campus, Richmond, VA 23298 USA

关键词: Amygdala;    Caudate-putamen;    GPCR;    neuroAIDS;    Nucleus accumbens;    DAMGO;    Morphine;    Autoradiography;    Desensitization;    Drug abuse;    Addiction;    Hippocampus;    Prefrontal cortex;   

DOI  :  10.1016/j.nbd.2016.01.014

来源: Elsevier

【 摘 要 】

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 mu-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 [S-35]guanosine-5'-O-(3-thio)triphosphate ([S-35]GTP gamma S) autoradiography in brain sections, and in concentration-effect curves of MOR agonist-stimulated [S-35]GTR gamma S binding in membranes isolated from specific brain regions. Comparative studies were done using the MOR-selective agonist DAMGO ([D-Ala(2), N-MePhe(4), 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 beta-arrestin-2, which is involved in MOR desensitization, were found to be elevated in only one affected brain region, the amygdala; amygdalar beta-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 beta-arrestin-2. (C) 2016 Published by Elsevier Inc.

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