title: 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.
abstract: 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 [(35)S]guanosine-5'-O-(3-thio)triphosphate ([(35)S]GTPγS) autoradiography in brain sections, and in concentration-effect curves of MOR agonist-stimulated [(35)S]GTPγS 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 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.
authors: Department of Anatomy & Neurobiology, Virginia Commonwealth University, Medical College of Virginia (MCV) Campus, Richmond, VA 23298-0709, USA.
authors: Yun K
authors: YK
authors: Hahn
authors: Department of Pharmacology & Toxicology, Virginia Commonwealth University, Medical College of Virginia (MCV) Campus, Richmond, VA 23298-0613, USA.
authors: Jason J
authors: JJ
authors: Paris
authors: Department of Pharmacology & Toxicology, Virginia Commonwealth University, Medical College of Virginia (MCV) Campus, Richmond, VA 23298-0613, USA; Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA 23298-0059, USA.
authors: Aron H
authors: AH
authors: Lichtman
authors: Department of Anatomy & Neurobiology, Virginia Commonwealth University, Medical College of Virginia (MCV) Campus, Richmond, VA 23298-0709, USA; Department of Pharmacology & Toxicology, Virginia Commonwealth University, Medical College of Virginia (MCV) Campus, Richmond, VA 23298-0613, USA; Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA 23298-0059, USA.
authors: Kurt F
authors: KF
authors: Hauser
authors: Department of Pharmacology & Toxicology, Virginia Commonwealth University, Medical College of Virginia (MCV) Campus, Richmond, VA 23298-0613, USA; Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA 23298-0059, USA.
authors: Laura J
authors: LJ
authors: Sim-Selley
authors: Department of Pharmacology & Toxicology, Virginia Commonwealth University, Medical College of Virginia (MCV) Campus, Richmond, VA 23298-0613, USA; Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA 23298-0059, USA.
authors: Dana E
authors: DE
authors: Selley
authors: Department of Anatomy & Neurobiology, Virginia Commonwealth University, Medical College of Virginia (MCV) Campus, Richmond, VA 23298-0709, USA; Department of Pharmacology & Toxicology, Virginia Commonwealth University, Medical College of Virginia (MCV) Campus, Richmond, VA 23298-0613, USA; Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA 23298-0059, USA. Electronic address: pamela.knapp@vcuhealth.org.
authors: Pamela E
authors: PE
authors: Knapp
mesh_terms: D015526:AIDS Dementia Complex / Q000378:metabolism; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001007:Anxiety / Q000378:metabolism* / Q000821:virology; D003213:Conditioning, Psychological / Q000502:physiology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D005239:Fear / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D015497:HIV-1; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009020:Morphine / Q000494:pharmacology; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism*; D000071560:beta-Arrestin 2 / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; C000605258:Arrb2 protein, mouse; D017450:Receptors, Opioid, mu; D000071560:beta-Arrestin 2; D054322:tat Gene Products, Human Immunodeficiency Virus; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009020:Morphine; D019204:GTP-Binding Proteins
keywords: Addiction; Amygdala; Autoradiography; Caudate–putamen; DAMGO; Desensitization; Drug abuse; GPCR; Hippocampus; Morphine; Nucleus accumbens; Prefrontal cortex; neuroAIDS