Opiate Drug Use and the Pathophysiology of NeuroAIDS

Current HIV Research

Volumn 10, Issue 5, 2012, Pages 435-452

  Hauser, Kurt F ^a,b   Fitting, Sylvia ^a   Dever, Seth M ^a   Podhaizer, Elizabeth M ^a   Knapp, Pamela E ^a,b  

^a VIRGINIA COMMONWEALTH UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b VIRGINIA COMMONWEALTH UNIVERSITY   (United States)

Author keywords

opioid receptors; Astroglia; CNS; HIV; HIV associated neurocognitive disorders (HAND); Microglia; Myelin; Neuroaids; Neuroimmunology; Neurotoxicity; Oligodendroglia; Opiate drug abuse; SIV

Indexed keywords

CHEMOKINE; CYTOKINE;

ACQUIRED IMMUNE DEFICIENCY SYNDROME; BRAIN CORTEX; CELL HETEROGENEITY; CENTRAL NERVOUS SYSTEM; COGNITIVE DEFECT; DEMYELINATION; DENDRITIC CELL; EXCITOTOXICITY; GLIA CELL; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; NEUROLOGIC DISEASE; NEUROTOXICITY; OLIGODENDROGLIA; OPIATE ADDICTION; PATHOPHYSIOLOGY; REVIEW; SYNAPSE;

ACQUIRED IMMUNODEFICIENCY SYNDROME; AIDS DEMENTIA COMPLEX; ASTROCYTES; FEMALE; HIV-1; HUMANS; MALE; MICROGLIA; NARCOTICS; NEUROGLIA; OPIOID-RELATED DISORDERS; SIGNAL TRANSDUCTION; SUBSTANCE-RELATED DISORDERS; TAT GENE PRODUCTS, HUMAN IMMUNODEFICIENCY VIRUS;

EID: 84866335871     PISSN: 1570162X     EISSN: 18734251     Source Type: Journal    
DOI: 10.2174/157016212802138779     Document Type: Review

References (307)

1. Bell JE, Brettle RP, Chiswick A, Simmonds P. HIV encephalitis, proviral load and dementia in drug users and homosexuals with AIDS. Effect of neocortical involvement. Brain 1998; 121: 2043-2052.
2. Anthony IC, Arango JC, Stephens B, Simmonds P, Bell JE. The effects of illicit drugs on the HIV infected brain. Front Biosci 2008; 13: 1294-1307.
3. Bell JE, Arango JC, Anthony IC. Neurobiology of multiple insults: HIV-1-associated brain disorders in those who use illicit drugs. J Neuroimmune Pharmacol 2006; 1: 182-191.
4. Anthony IC, Ramage SN, Carnie FW, Simmonds P, Bell JE. Does drug abuse alter microglial phenotype and cell turnover in the context of advancing HIV infection? Neuropathol Appl Neurobiol 2005; 31: 325-338.
5. Arango JC, Simmonds P, Brettle RP, Bell JE. Does drug abuse influence the microglial response in AIDS and HIV encephalitis? AIDS 2004; 18 Suppl 1: S69-S74.
6. Cohen RA. The Changing Face of HIV-Associated Cognitive and Neuropsychiatric Disturbance. In: Paul RH, Sacktor NC, Valcour V, Tashima KT, editors. HIV and the Brain: New Challenges in the Modern Era. 1 ed. New York: Humana Press Inc 2009; 133-186.
7. Martin-Thormeyer EM, Paul RH. Drug abuse and hepatitis C infection as comorbid features of HIV associated neurocognitive disorder: neurocognitive and neuroimaging features. Neuropsychol Rev 2009; 19: 215-231.
8. Byrd DA, Fellows RP, Morgello S, et al. Neurocognitive impact of substance use in HIV infection. J Acquir Immune Defic Syndr 2011; 58: 154-162.
9. Antinori A, Arendt G, Becker JT, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology 2007; 69: 1789-1799.
10. Valcour V, Sithinamsuwan P, Letendre S, Ances B. Pathogenesis of HIV in the Central Nervous System. Curr HIV/AIDS Rep 2011; 8: 54-61.
11. McArthur JC, Steiner J, Sacktor N, Nath A. Human immunodeficiency virus-associated neurocognitive disorders: Mind the gap. Ann Neurol 2010; 67: 699-714.
12. Banerjee A, Strazza M, Wigdahl B, Pirrone V, Meucci O, Nonnemacher MR. Role of mu-opioids as cofactors in human immunodeficiency virus type 1 disease progression and neuropathogenesis. J Neurovirol 2011; 17: 291-302.
13. Hauser KF, El-Hage N, Bruce-Keller A, Knapp PE. Opioids, astroglial chemokines, microglial reactivity, and neuronal injury in HIV-1 encephalitis. In: Meucci O, editor. Chemokine Receptors and NeuroAIDS: Beyond Co-Receptor Function and Links to Other Neuropathologies. 1 ed. New York: Springer 2010: p. 353-378.
14. Akil H, Watson SJ, Young E, Lewis ME, Khachaturian H, Walker JM. Endogenous opioids: biology and function. Ann Rev Neurosci 1984; 7: 223-255.
15. Hutchinson MR, Shavit Y, Grace PM, Rice KC, Maier SF, Watkins LR. Exploring the neuroimmunopharmacology of opioids: an integrative review of mechanisms of central immune signaling and their implications for opioid analgesia. Pharmacol Rev 2011; 63: 772-810.
16. Christie MJ. Cellular neuroadaptations to chronic opioids: tolerance, withdrawal and addiction. Br J Pharmacol 2008; 154: 384-396.
17. Stefano GB, Kream R. Endogenous opiates, opioids, and immune function: evolutionary brokerage of defensive behaviors. Semin Cancer Biol 2008; 18: 190-198.
18. Bidlack JM, Khimich M, Parkhill AL, Sumagin S, Sun B, Tipton CM. Opioid receptors and signaling on cells from the immune system. J Neuroimmune Pharmacol 2006; 1: 260-269.
19. Evans CJ. Secrets of the opium poppy revealed. Neuropharmacology 2004; 47 Suppl 1: 293-299.
20. McCarthy L, Wetzel M, Sliker JK, Eisenstein TK, Rogers TJ. Opioids, opioid receptors, and the immune response. Drug Alcohol Depend 2001; 62: 111-123.
21. Wright CI. The enzymatic deacetylation of heroin and related morphine derivatives by blood serum. J Pharmacol Exp Ther 1941; 71: 164-177.
22. Jaffe JH, Martin WR. Opioid analgesics and antagonists. In: Gilman AG, Goodman LS, Rall TW, Murad F, editors. The Pharmacological Basis of Therapeutics. 7 ed. New York: MacMillan Publishing Co 1985; p. 491-531.
23. Thompson KA, Cherry CL, Bell JE, McLean CA. Brain cell reservoirs of latent virus in presymptomatic HIV-infected individuals. Am J Pathol 2011; 179: 1623-1629.
24. Squinto SP, Mondal D, Block AL, Prakash O. Morphine-induced transactivation of HIV-1 LTR in human neuroblastoma cells. AIDS Res Hum Retroviruses 1990; 6: 1163-1168.
25. Marcario JK, Riazi M, Adany I, et al. Effect of morphine on the neuropathogenesis of SIVmac infection in Indian Rhesus Macaques. J Neuroimmune Pharmacol 2008; 3: 12-15.
26. Bokhari SM, Hegde R, Callen S, et al. Morphine potentiates neuropathogenesis of SIV infection in Rhesus macaques. J Neuroimmune Pharmacol 2011; 6: 626-639.
27. Perez-Casanova A, Husain K, Noel RJ, Jr., Rivera-Amill V, Kumar A. Interaction of SIV/SHIV infection and morphine on plasma oxidant/antioxidant balance in macaque. Mol Cell Biochem 2008; 308: 169-175.
28. Perez-Casanova A, Noel RJ, Jr., Rivera-Amill V, Husain K, Kumar A. Morphine-mediated deterioration of oxidative stress leads to rapid disease progression in SIV/SHIV-infected macaques. AIDS Res Hum Retroviruses 2007; 23: 1004-1007.
29. Kumar R, Orsoni S, Norman L, et al. Chronic morphine exposure causes pronounced virus replication in cerebral compartment and accelerated onset of AIDS in SIV/SHIV-infected Indian rhesus macaques. Virology 2006; 354: 192-206.
30. Noel RJ, Jr., Kumar A. SIV Vpr evolution is inversely related to disease progression in a morphine-dependent rhesus macaque model of AIDS. Virology 2007; 359: 397-404.
31. Rivera-Amill V, Noel RJ, Jr., Orsini S, et al. Variable region 4 of SIV envelope correlates with rapid disease progression in morphine-exposed macaques infected with SIV/SHIV. Virology 2007; 358: 373-383.
32. Noel RJ, Jr., Marrero-Otero Z, Kumar R, Chompre-Gonzalez GS, Verma AS, Kumar A. Correlation between SIV Tat evolution and AIDS progression in cerebrospinal fluid of morphine-dependent and control macaques infected with SIV and SHIV. Virology 2006; 349: 440-452.
33. Newsome SD, Johnson E, Pardo C, McArthur JC, Nath A. Fulminant encephalopathy with basal ganglia hyperintensities in HIV-infected drug users. Neurology 2011; 76: 787-794.
34. Royal W 3rd, Updike M, Selnes OA, et al. HIV-1 infection and nervous system abnormalities among a cohort of intravenous drug users. Neurology 1991; 41: 1905-110.
35. Martin EM, Pitrak DL, Rains N, et al. Delayed nonmatch-tosample performance in HIV-seropositive and HIV-seronegative polydrug abusers. Neuropsychology 2003; 17: 283-288.
36. Donahoe RM, Vlahov D. Opiates as potential cofactors in progression of HIV-1 infections to AIDS. J Neuroimmunol 1998; 83: 77-87.
37. Everall IP. Interaction between HIV and intravenous heroin abuse? J Neuroimmunol 2004; 147: 13-15.
38. Nath A. Human immunodeficiency virus-associated neurocognitive disorder: pathophysiology in relation to drug addiction. Ann N Y Acad Sci 2010; 1187: 122-128.
39. Hauser KF, El-Hage N, Stiene-Martin A, et al. HIV-1 neuropathogenesis: Glial mechanisms revealed through substance abuse. J Neurochem 2007; 100: 567-586.
40. Kreek MJ, Nielsen DA, Butelman ER, LaForge KS. Genetic influences on impulsivity, risk taking, stress responsivity and vulnerability to drug abuse and addiction. Nat Neurosci 2005; 8: 1450-1457.
41. Moore DJ, Arce M, Moseley S, et al. Family history of dementia predicts worse neuropsychological functioning among HIV infected persons. J Neuropsychiatry Clin Neurosci 2011; 23: 316-323.
42. Crystal HA, Hamon S, Randesi M, et al. A C17T polymorphism in the mu opiate receptor is associated with quantitative measures of drug use in African American women. Addict Biol 2012; 17: 181-191.
43. Klepstad P, Rakvag TT, Kaasa S, et al. The 118 A > G polymorphism in the human mu-opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease. Acta Anaesthesiol Scand 2004; 48: 1232-1239.
44. Yuferov V, Levran O, Proudnikov D, Nielsen DA, Kreek MJ. Search for genetic markers and functional variants involved in the development of opiate and cocaine addiction and treatment. Ann N Y Acad Sci 2010; 1187: 184-207.
45. Regan PM, Dave RS, Datta PK, Khalili K. Epigenetics of microopioid receptors: Intersection with HIV-1 infection of the central nervous system. J Cell Physiol 2012; 227: 2832-28741.
46. Faure S, Meyer L, Costagliola D, et al. Rapid progression to AIDS in HIV+ individuals with a structural variant of the chemokine receptor CX3CR1. Science 2000; 287: 2274-2277.
47. Hladik F, Liu H, Speelmon E, et al. Combined effect of CCR5- Delta32 heterozygosity and the CCR5 promoter polymorphism - 2459 A/G on CCR5 expression and resistance to human immunodeficiency virus type 1 transmission. J Virol 2005; 79: 11677-11684.
48. Berger EA, Murphy PM, Farber JM. Chemokine receptors as HIV- 1 coreceptors: roles in viral entry, tropism, and disease. Annu Rev Immunol 1999; 17: 657-700.
49. Gonzalez E, Rovin BH, Sen L, et al. HIV-1 infection and AIDS dementia are influenced by a mutant MCP-1 allele linked to increased monocyte infiltration of tissues and MCP-1 levels. Proc Natl Acad Sci USA 2002; 99: 13795-800.
50. Turchan-Cholewo J, Liu Y, Gartner S, et al. Increased vulnerability of ApoE4 neurons to HIV proteins and opiates: protection by diosgenin and L-deprenyl. Neurobiol Dis 2006; 23: 109-119.
51. Corder EH, Robertson K, Lannfelt L, et al. HIV-infected subjects with the E4 allele for APOE have excess dementia and peripheral neuropathy. Nat Med 1998; 4: 1182-1184.
52. Andres MA, Feger U, Nath A, Munsaka S, Jiang CS, Chang L. APOE epsilon 4 allele and CSF APOE on cognition in HIVinfected subjects. J Neuroimmune Pharmacol 2011; 6: 389-398.
53. Wee S, Koob GF. The role of the dynorphin-kappa opioid system in the reinforcing effects of drugs of abuse. Psychopharmacology (Berl) 2010; 210: 121-135.
54. Clarke TK, Krause K, Li T, Schumann G. An association of prodynorphin polymorphisms and opioid dependence in females in a Chinese population. Addict Biol 2009; 14: 366-370.
55. Wei SG, Zhu YS, Lai JH, Xue HX, Chai ZQ, Li SB. Association between heroin dependence and prodynorphin gene polymorphisms. Brain Res Bull 2011; 85: 238-242.
56. Yuferov V, Ji F, Nielsen DA, et al. A functional haplotype implicated in vulnerability to develop cocaine dependence is associated with reduced PDYN expression in human brain. Neuropsychopharmacology 2009; 34: 1185-1197.
57. Drakenberg K, Nikoshkov A, Horvath MC, et al. Mu opioid receptor A118G polymorphism in association with striatal opioid neuropeptide gene expression in heroin abusers. Proc Natl Acad Sci USA 2006; 103: 7883-7888.
58. Shippenberg TS, Zapata A, Chefer VI. Dynorphin and the pathophysiology of drug addiction. Pharmacol Ther 2007; 116: 306-321.
59. Rook EJ, Huitema AD, van den Brink W, Van Ree JM, Beijnen JH. Pharmacokinetics and pharmacokinetic variability of heroin and its metabolites: review of the literature. Curr Clin Pharmacol 2006; 1: 109-118.
60. Podhaizer EM, Zou S, Fitting S, et al. Morphine and gp120 toxic interactions in striatal neurons are dependent on HIV-1 strain. J Neuroimmune Pharmacol 2012; in press, DOI: 10.1007/s11481-011-9326-z.
61. Turchan-Cholewo J, Dimayuga FO, Gupta S, et al. Morphine and HIV-Tat increase microglial-free radical production and oxidative stress: possible role in cytokine regulation. J Neurochem 2009; 108: 202-215.
62. Hauser KF, El-Hage N, Buch S, et al. Impact of opiate-HIV-1 interactions on neurotoxic signaling. J Neuroimmune Pharmacol 2006; 1: 98-105.
63. Hauser KF, El-Hage N, Buch S, et al. Molecular targets of opiate drug abuse in neuro AIDS. Neurotox Res 2005; 8: 63-80.
64. Nath A, Hauser KF, Wojna V, et al. Molecular basis for interactions of HIV and drugs of abuse. J Acquir Immune Defic Syndr 2002; 31 Suppl 2: S62-S69.
65. Nath A, Jones M, Maragos W, et al. Neurotoxicity and dysfunction of dopamine systems associated with AIDS dementia. Psychopharmacol 2000; 14: 222-227.
66. Bruce-Keller AJ, Turchan-Cholewo J, Smart EJ, et al. Morphine causes rapid increases in glial activation and neuronal injury in the striatum of inducible HIV-1 Tat transgenic mice. Glia 2008; 56: 1414-1427.
67. Gurwell JA, Nath A, Sun Q, et al. Synergistic neurotoxicity of opioids and human immunodeficiency virus-1 Tat protein in striatal neurons in vitro. Neuroscience 2001; 102: 555-563.
68. Malik S, Khalique H, Buch S, Seth P. A growth factor attenuatesHIV-1 Tat and morphine induced damage to human neurons: implication in HIV/AIDS-drug abuse cases. PLoS One 2011; 6: e18116.
69. Hu S, Sheng WS, Lokensgard JR, Peterson PK. Morphine potentiates HIV-1 gp120-induced neuronal apoptosis. J Infect Dis 2005; 191: 886-889.
70. El-Hage N, Bruce-Keller AJ, Yakovleva T, Bakalkin G, Knapp PE, Hauser KF. Morphine exacerbates HIV-1 Tat-induced cytokine production in astrocytes through convergent effects on [Ca2+]i, NF- kκ B trafficking and transcription. PLoS One 2008; 3: e4093.
71. El-Hage N, Wu G, Wang J, et al. HIV-1 Tat and opiate-induced changes in astrocytes promote chemotaxis of microglia through the expression of MCP-1 and alternative chemokines. Glia 2006; 53: 132-146.
72. El-Hage N, Gurwell JA, Singh IN, Knapp PE, Nath A, Hauser KF. Synergistic increases in intracellular Ca2+, and the release of MCP- 1, RANTES, and IL-6 by astrocytes treated with opiates and HIV-1 Tat. Glia 2005; 50: 91-106.
73. Stiene-Martin A, Zhou R, Hauser KF. Regional, developmental, and cell cycle-dependent differences in μ, δ, and κ-opioid receptor expression among cultured mouse astrocytes. Glia 1998; 22: 249-259.
74. Hauser KF, Harris-White ME, Jackson JA, Opanashuk LA, Carney JM. Opioids disrupt Ca2+ homeostasis and induce carbonyl oxyradical production in mouse astrocytes in vitro: transient increases and adaptation to sustained exposure. Exp Neurol 1998; 151: 70-76.
75. Gurwell JA, Duncan MJ, Maderspach K, Stiene-Martin A, Elde RP, Hauser KF. κ-Opioid receptor expression defines a phenotypically distinct subpopulation of astroglia: relationship to Ca2+ mobilization, development, and the antiproliferative effect of opioids. Brain Res 1996; 737: 175-187.
76. Hauser KF, Stiene-Martin A, Mattson MP, Elde RP, Ryan SE, Godleske CC. μ -Opioid receptor-induced Ca2+ mobilization and astroglial development: Morphine inhibits DNA synthesis and stimulates cellular hypertrophy through a Ca2+-dependent mechanism. Brain Res 1996; 720: 191-203.
77. Stiene-Martin A, Mattson MP, Hauser KF. Opiates selectively increase intracellular calcium in developing type 1 astrocytes: Role of calcium in morphine-induced morphologic differentiation. Dev Brain Res 1993; 76: 189-196.
78. Stiene-Martin A, Gurwell JA, Hauser KF. Morphine alters astrocyte growth in primary cultures of mouse glial cells: Evidence for a direct effect of opiates on neural maturation. Dev Brain Res 1991; 60: 1-7.
79. auser KF, Osborne JG, Stiene-Martin A, Melner MH. Cellular localization of proenkephalin mRNA and enkephalin peptide products in cultured astrocytes. Brain Res 1990; 522: 347-353.
80. Gupta S, Knight AG, Gupta S, et al. HIV-Tat elicits microglial glutamate release: role of NAPDH oxidase and the cystineglutamate antiporter. Neurosci Lett 2010; 485: 233-236.
81. Turchan-Cholewo J, Dimayuga FO, Ding Q, et al. Cell-specific actions of HIV-Tat and morphine on opioid receptor expression in glia. J Neurosci Res 2008; 86: 2100-2110.
82. El-Hage N, Bruce-Keller AJ, Knapp PE, Hauser KF. CCL5/RANTES gene deletion attenuates opioid-induced increases in glial CCL2/MCP-1 immunoreactivity and activation in HIV-1 Tat exposed mice. J Neuroimmune Pharmacol 2008; 3: 275-285.
83. Hauser KF, Hahn YK, Adjan VV, et al. HIV-1 Tat and morphine have interactive effects on oligodendrocyte survival and morphology. Glia 2009; 57: 194-206.
84. Buch SK, Khurdayan VK, Lutz SE, Knapp PE, El-Hage N, Hauser KF. Glial-restricted precursors: Patterns of expression of opioid receptors and relationship to HIV-1 Tat and morphine susceptibility in vitro. Neuroscience 2007; 146: 1546-1554.
85. Khurdayan VK, Buch S, El-Hage N, et al. Preferential vulnerability of astroglia and glial precursors to combined opioid and HIV-1 Tat exposure in vitro. Eur J Neurosci 2004; 19: 3171-3182.
86. Fitting S, Zou S, Chen W, Vo P, Hauser KF, Knapp PE. Regional Heterogeneity and diversity in cytokine and chemokine production by astroglia: differential responses to HIV-1 Tat, gp120 and morphine revealed by multiplex analysis. J Proteome Res 2010; 9: 1795-1804.
87. Oehmichen M, Meissner C, Reiter A, Birkholz M. Neuropathology in non-human immunodeficiency virus-infected drug addicts: hypoxic brain damage after chronic intravenous drug abuse. Acta Neuropathol (Berl) 1996; 91: 642-696.
88. Rizzuto N, Morbin M, Ferrari S, et al. Delayed spongiform leukoencephalopathy after heroin abuse. Acta Neuropathol (Berl) 1997; 94: 87-90.
89. Buttner A, Mall G, Penning R, Weis S. The neuropathology of heroin abuse. Forensic Sci Int 2000; 113: 435-442.
90. Buttner A. The Neuropathology of Drug Abuse. Neuropathol Appl Neurobiol 2011; 37: 118-134.
91. Kish SJ, Kalasinsky KS, Derkach P, et al. Striatal dopaminergic and serotonergic markers in human heroin users. Neuropsychopharmacology 2001; 24: 561-567.
92. Makrigeorgi-Butera M, Hagel C, Laas R, Puschel K, Stavrou D. Comparative brain pathology of HIV-seronegative and HIVinfected drug addicts. Clin Neuropathol 1996; 15: 324-329.
93. Anthony IC, Norrby KE, Dingwall T, et al. Predisposition to accelerated Alzheimer-related changes in the brains of human immunodeficiency virus negative opiate abusers. Brain 2010; 133: 3685-3698.
94. Ramage SN, Anthony IC, Carnie FW, Busuttil A, Robertson R, Bell JE. Hyperphosphorylated tau and amyloid precursor protein deposition is increased in the brains of young drug abusers. Neuropathol Appl Neurobiol 2005; 31: 439-448.
95. Zou S, Fitting S, Hahn YK, et al. Morphine potentiates neurodegenerative effects of HIV-1 Tat through actions at μ-opioid receptor-expressing glia. Brain 2011; 134: 3613-3628.
96. Suzuki M, El-Hage N, Zou S, et al. Fractalkine/CX3CL1 protects striatal neurons from synergistic morphine and HIV-1 Tat-induced dendritic losses and death. Mol Neurodegener 2011; 6: 78.
97. Bakalkin G, Watanabe H, Jezierska J, et al. Prodynorphin mutations cause the neurodegenerative disorder spinocerebellar ataxia type 23. Am J Hum Genet 2010; 87: 593-603.
98. Purves D, Lichtman JW. Elimination of synapses in the developing nervous system. Science 1980; 210: 153-157.
99. Mattson MP, Kater SB. Excitatory and inhibitory neurotransmitters in the generation and degeneration of hippocampal neuroarchitecture. Brain Res 1989; 478: 337-348.
100. Mattson MP, Dou P, Kater SB. Outgrowth-regulating actions of glutamate in isolated hippocampal pyramidal neurons. J Neurosci 1988; 8: 2087-2100.
101. Mattson MP, Kater SB. Calcium regulation of neurite elongation and growth cone motility. J Neurosci 1987; 7: 4034-4043.
102. Liao D, Grigoriants OO, Wang W, Wiens K, Loh HH, Law PY. Distinct effects of individual opioids on the morphology of spines depend upon the internalization of mu opioid receptors. Mol Cell Neurosci 2007; 35: 456-469.
103. Liao D, Grigoriants OO, Loh HH, Law PY. Agonist-dependent postsynaptic effects of opioids on miniature excitatory postsynaptic currents in cultured hippocampal neurons. J Neurophysiol 2007; 97: 1485-1494.
104. Liao D, Lin H, Law PY, Loh HH. Mu-opioid receptors modulate the stability of dendritic spines. Proc Natl Acad Sci USA 2005; 102: 1725-1730.
105. Lichtman JW, Denk W. The big and the small: challenges of imaging the brain's circuits. Science 2011; 334: 618-623.
106. Zou S, El-Hage N, Podhaizer EM, Knapp PE, Hauser KF. PTEN gene silencing prevents HIV-1 gp120IIIB-induced degeneration of striatal neurons. J Neurovirol 2011; 17: 41-49.
107. McCobb DP, Cohan CS, Connor JA, Kater SB. Interactive effects of serotonin and acetylcholine on neurite elongation. Neuron 1988; 1: 377-385.
108. Singh IN, El-Hage N, Campbell ME, et al. Differential involvement of p38 and JNK MAP kinases in HIV-1 Tat and gp120-induced apoptosis and neurite degeneration in striatal neurons. Neuroscience 2005; 135: 781-790.
109. Singh IN, Goody RJ, Dean C, et al. Apoptotic death of striatal neurons induced by HIV-1 Tat and gp120: differential involvement of caspase-3 and endonuclease G. J Neurovirol 2004; 10: 141-151.
110. Keppel G. Design and Analysis: A Rresearcher's Handbook 3 ed. Upper Saddle River, NJ: Prentice Hall; 1991.
111. Kramer-Hammerle S, Rothenaigner I, Wolff H, Bell JE, Brack-Werner R. Cells of the central nervous system as targets and reservoirs of the human immunodeficiency virus. Virus Res 2005; 111: 194-213.
112. Lawrence DM, Durham LC, Schwartz L, Seth P, Maric D, Major EO. Human immunodeficiency virus type 1 infection of human brain-derived progenitor cells. J Virol 2004; 78: 7319-7328.
113. Li J, Bentsman G, Potash MJ, Volsky DJ. Human immunodeficiency virus type 1 efficiently binds to human fetal astrocytes and induces neuroinflammatory responses independent of infection. BMC Neurosci 2007; 8: 31.
114. Ghafouri M, Amini S, Khalili K, Sawaya BE. HIV-1 associated dementia: symptoms and causes. Retrovirology 2006; 19: 28.
115. Kaul M, Garden GA, Lipton SA. Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 2001; 410: 988-994.
116. Gonzalez-Scarano F, Martin-Garcia J. The neuropathogenesis of AIDS. Nat Rev Immunol 2005; 5: 69-81.
117. Kaul M, Ma Q, Medders KE, Desai MK, Lipton SA. HIV-1 coreceptors CCR5 and CXCR4 both mediate neuronal cell death but CCR5 paradoxically can also contribute to protection. Cell Death Differ 2007; 14: 296-305.
118. Masliah E, Ge N, Morey M, DeTeresa R, Terry RD, Wiley CA. Cortical dendritic pathology in human deficiency virus encephalitis. Laboratory Investigation 1992; 66: 285-291.
119. Masliah E, Heaton RK, Marcotte TD, et al. Dendritic injury is a pathological substrate for human immunodeficiency virus-related cognitive disorders. HNRC Group. The HIV Neurobehavioral Research Center. Ann Neurol 1997; 42: 963-972.
120. Sa MJ, Madeira MD, Ruela C, Volk B, Mota-Miranda A, Paula-Barbosa MM. Dendritic changes in the hippocampal formation of AIDS patients: a quantitative Golgi study. Acta Neuropathol (Berl) 2004; 107: 97-110.
121. Everall IP. Neuronal damage - recent issues and implications for therapy. J Neurovirol 2000; 6 Suppl 1: S103-S105.
122. Everall IP, Heaton RK, Marcotte TD, et al. Cortical synaptic density is reduced in mild to moderate human immunodeficiency virus neurocognitive disorder. HNRC Group. HIV Neurobehavioral Research Center. Brain Pathol 1999; 9: 209-217.
123. Ellis R, Langford D, Masliah E. HIV and antiretroviral therapy in the brain: neuronal injury and repair. Nat Rev Neurosci 2007; 8: 33-44.
124. Fitting S, Xu R, Bull CM, et al. Interactive comorbidity between opioid drug abuse and HIV-1 Tat: Chronic exposure augments spine loss and sublethal dendritic pathology in striatal neurons. Am J Pathol 2010; 177: 1397-1410.
125. Mattson MP, Haughey NJ, Nath A. Cell death in HIV dementia. Cell Death Differ 2005; 12: 893-904.
126. Li W, Huang Y, Reid R, et al. NMDA receptor activation by HIVTat protein is clade dependent. J Neurosci 2008; 28: 12190-8.
127. Bursztajn S, Rutkowski MD, DeLeo JA. The role of the N-methyl- D-aspartate receptor NR1 subunit in peripheral nerve injuryinduced mechanical allodynia, glial activation and chemokine expression in the mouse. Neuroscience 2004; 125: 269-275.
128. Adam F, Dufour E, Le Bars D. The glycine site-specific NMDA antagonist (+)-HA966 enhances the effect of morphine and reverses morphine tolerance via a spinal mechanism. Neuropharmacology 2008; 54: 588-596.
129. Song L, Nath A, Geiger JD, Moore A, Hochman S. Human immunodeficiency virus type 1 Tat protein directly activates neuronal N-methyl-D-aspartate receptors at an allosteric zincsensitive site. J Neurovirol 2003; 9: 399-403.
130. Haughey NJ, Nath A, Mattson MP, Slevin JT, Geiger JD. HIV-1 Tat through phosphorylation of NMDA receptors potentiates glutamate excitotoxicity. J Neurochem 2001; 78: 457-467.
131. Chen W, Tang Z, Fortina P, et al. Ethanol potentiates HIV-1 gp120-induced apoptosis in human neurons via both the death receptor and NMDA receptor pathways. Virology 2005; 334: 59-73.
132. Bennett BA, Rusyniak DE, Hollingsworth CK. HIV-1 gp120- induced neurotoxicity to midbrain dopamine cultures. Brain Res 1995; 705: 168-176.
133. Meucci O, Miller RJ. Gp120-induced neurotoxicity in hippocampal pyramidal neuron cultures: protective action of TGF-beta1. J Neurosci 1996; 16: 4080-4088.
134. Lannuzel A, Lledo PM, Lamghitnia HO, Vincent JD, Tardieu M. HIV-1 envelope proteins gp120 and gp160 potentiate NMDAinduced [Ca2+]i increase, alter [Ca2+]i homeostasis and induce neurotoxicity in human embryonic neurons. Eur J Neurosci 1995; 7: 2285-2293.
135. Lipton SA. Memantine prevents HIV coat protein-induced neuronal injury in vitro. Neurology 1992; 42: 1403-1405.
136. Lipton SA, Sucher NJ, Kaiser PK, Dreyer EB. Synergistic effects of HIV coat protein and NMDA receptor-mediated neurotoxicity. Neuron 1991; 7: 111-118.
137. Eugenin EA, King JE, Nath A, et al. HIV-tat induces formation of an LRP-PSD-95- NMDAR-nNOS complex that promotes apoptosis in neurons and astrocytes. Proc Natl Acad Sci USA 2007; 104: 3438-3443.
138. Perry SW, Norman JP, Gelbard HA. Adjunctive therapies for HIV- 1 associated neurologic disease. Neurotox Res 2005; 8: 161-166.
139. Norman JP, Perry SW, Kasischke KA, Volsky DJ, Gelbard HA. HIV-1 trans activator of transcription protein elicits mitochondrial hyperpolarization and respiratory deficit, with dysregulation of complex IV and nicotinamide adenine dinucleotide homeostasis in cortical neurons. J Immunol 2007; 178: 869-876.
140. Nath A, Conant K, Chen P, Scott C, Major EO. Transient exposure to HIV-1 Tat protein results in cytokine production in macrophages and astrocytes: A hit and run phenomenon. J Biol Chem 1999; 274: 17098-17102.
141. Maggirwar SB, Tong N, Ramirez S, Gelbard HA, Dewhurst S. HIV-1 Tat-mediated activation of glycogen synthase kinase-3beta contributes to Tat-mediated neurotoxicity. J Neurochem 1999; 73: 578-586.
142. Nath A. Human immunodeficiency virus (HIV) proteins in neuropathogenesis of HIV dementia. J Infect Dis 2002; 186 Suppl 2: S193-S198.
143. Mattson MP, Gleichmann M, Cheng A. Mitochondria in neuroplasticity and neurological disorders. Neuron 2008; 60: 748-766.
144. Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 2006; 443: 787-795.
145. Oliva AA, Jr., Lam TT, Swann JW. Distally directed dendrotoxicity induced by kainic acid in hippocampal interneurons of green fluorescent protein-expressing transgenic mice. J Neurosci 2002; 22: 8052-8062.
146. Greenwood SM, Connolly CN. Dendritic and mitochondrial changes during glutamate excitotoxicity. Neuropharmacology 2007; 53: 891-898.
147. Yang Y, Fukui K, Koike T, Zheng X. Induction of autophagy in neurite degeneration of mouse superior cervical ganglion neurons. Eur J Neurosci 2007; 26: 2979-2988.
148. Park JS, Bateman MC, Goldberg MP. Rapid alterations in dendrite morphology during sublethal hypoxia or glutamate receptor activation. Neurobiol Dis 1996; 3: 215-227.
149. Greenwood SM, Mizielinska SM, Frenguelli BG, Harvey J, Connolly CN. Mitochondrial dysfunction and dendritic beading during neuronal toxicity. J Biol Chem 2007; 282: 26235-26244.
150. Yang Y, Xu K, Koike T, Zheng X. Transport of autophagosomes in neurites of PC12 cells during serum deprivation. Autophagy 2008; 4: 243-245.
151. Bellizzi MJ, Lu SM, Masliah E, Gelbard HA. Synaptic activity becomes excitotoxic in neurons exposed to elevated levels of platelet-activating factor. J Clin Invest 2005; 115: 3185-3192.
152. Mattson MP, Duan W. "Apoptotic" biochemical cascades in synaptic compartments: roles in adaptive plasticity and neurodegenerative disorders. J Neurosci Res 1999; 58: 152-166.
153. Mattson MP, Keller JN, Begley JG. Evidence for synaptic apoptosis. Exp Neurol 1998; 153: 35-48.
154. van Grol J., Subauste C, Andrade RM, Fujinaga K, Nelson J, Subauste CS. HIV-1 inhibits autophagy in bystander macrophage/monocytic cells through Src-Akt and STAT3. PLoS One 2010; 5: e11733.
155. Norman JP, Perry SW, Reynolds HM, et al. HIV-1 Tat activates neuronal ryanodine receptors with rapid induction of the unfolded protein response and mitochondrial hyperpolarization. PLoS One 2008; 3: e3731.
156. Li JC, Au KY, Fang JW, et al. HIV-1 trans-activator protein dysregulates IFN-γ signaling and contributes to the suppression of autophagy induction. AIDS 2011; 25: 15-25.
157. Espert L, Varbanov M, Robert-Hebmann V, et al. Differential role of autophagy in CD4 T cells and macrophages during X4 and R5 HIV-1 infection. PLoS One 2009; 4: e5787.
158. Espert L, Denizot M, Grimaldi M, et al. Autophagy is involved in T cell death after binding of HIV-1 envelope proteins to CXCR4. J Clin Invest 2006; 116: 2161-2172.
159. Zhao L, Zhu Y, Wang D, et al. Morphine induces Beclin 1- and ATG5-dependent autophagy in human neuroblastoma SH-SY5Y cells and in the rat hippocampus. Autophagy 2010; 6: 386-394.
160. Hauser KF, McLaughlin PJ, Zagon IS. Endogenous opioid systems and the regulation of dendritic growth and spine formation. J Comp Neurol 1989; 281: 13-22.
161. Hauser KF, McLaughlin PJ, Zagon IS. Endogenous opioids regulate dendritic growth and spine formation in developing rat brain. Brain Res 1987; 416: 157-161.
162. Hauser KF, Gurwell JA, Turbek CS. Morphine inhibits Purkinje cell survival and dendritic differentiation in organotypic cultures of the mouse cerebellum. Exp Neurol 1994; 130: 95-105.
163. Robinson TE, Kolb B. Structural plasticity associated with exposure to drugs of abuse. Neuropharmacology 2004; 47 Suppl 1: 33-46.
164. Robinson TE, Kolb B. Morphine alters the structure of neurons in the nucleus accumbens and neocortex of rats. Synapse 1999; 33: 160-162.
165. Seatriz JV, Hammer RP, Jr. Effects of opiates on neuronal development in the rat cerebral cortex. Brain Res Bull 1993; 30: 523-527.
166. Hammer RP, Jr., Hauser KF. Consequences of early exposure to opioids on cell proliferation and neuronal morphogenesis. In: Miller MW, editor. Development of the Central Nervous System: Effects of Alcohol and Opiates. New York: Wiley-Liss; 1992: p 319-339.
167. Ricalde AA, Hammer RP, Jr. Perinatal opiate treatment delays growth of cortical dendrites. Neurosci Lett 1991; 115: 137-143.
168. Zheng H, Chu J, Zeng Y, Loh HH, Law PY. Yin Yang 1 phosphorylation contributes to the differential effects of mu-opioid receptor agonists on microRNA-190 expression. J Biol Chem 2010; 285: 21994-2002.
169. Zheng H, Chu J, Zhang Y, Loh HH, Law PY. Modulating μ-opioid receptor phosphorylation switches agonist-dependent signaling as reflected in PKCε activation and dendritic spine stability. J Biol Chem 2011; 286: 12724-12733.
170. Zheng H, Zeng Y, Chu J, Kam AY, Loh HH, Law PY. Modulations of NeuroD activity contribute to the differential effects of morphine and fentanyl on dendritic spine stability. J Neurosci 2010; 30: 8102-8110.
171. Luscher C, Slesinger PA. Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease. Nat Rev Neurosci 2010; 11: 301-315.
172. Mathews JL, Smrcka AV, Bidlack JM. A novel Gbetagammasubunit inhibitor selectively modulates mu-opioid-dependent antinociception and attenuates acute morphine-induced antinociceptive tolerance and dependence. J Neurosci 2008; 28: 12183-12189.
173. Bonacci TM, Mathews JL, Yuan C, et al. Differential targeting of Gbetagamma-subunit signaling with small molecules. Science 2006; 312: 443-446.
174. Haughey NJ, Holden CP, Nath A, Geiger JD. Involvement of inositol 1,4,5-trisphosphate-regulated stores of intracellular calcium in calcium dysregulation and neuron cell death caused by HIV-1 Protein Tat. J Neurochem 1999; 73: 1363-1374.
175. Conant K, Ma M, Nath A, Major EO. Extracellular human immunodeficiency virus type 1 Tat protein is associated with an increase in both NF-kappa B binding and protein kinase C activity in primary human astrocytes. J Virol 1996; 70: 1384-1389.
176. Kutsch O, Oh J, Nath A, Benveniste EN. Induction of the chemokines interleukin-8 and IP-10 by human immunodeficiency virus type 1 tat in astrocytes. J Virol 2000; 74: 9214-9221.
177. Conant K, Garzino-Demo A, Nath A, et al. Induction of monocyte chemoattractant protein-1 in HIV-1 Tat-stimulated astrocytes and elevation in AIDS dementia. Proc Natl Acad Sci USA 1998; 95: 3117-3121.
178. Benos DJ, Hahn BH, Shaw GM, Bubien JK, Benveniste EN. gp120-mediated alterations in astrocyte ion transport. Adv Neuroimmunol 1994; 4: 175-179.
179. Benos DJ, McPherson S, Hahn BH, Chaikin MA, Benveniste EN. Cytokines and HIV envelope glycoprotein gp120 stimulate Na+/H+ exchange in astrocytes. J Biol Chem 1994; 269: 13811-6.
180. Holden CP, Nath A, Haughey NJ, Geiger JD. Involvement of Na+/H+ exchangers, Ca2+ channels, and excitatory amino acid receptors in intracellular Ca2+ responses to HIV-1 gp120 in cultured human fetal brain cells. Neuroscience 1999; 91: 1369-1378.
181. Mahajan SD, Aalinkeel R, Reynolds JL, et al. Morphine exacerbates HIV-1 viral protein gp120 induced modulation of chemokine gene expression in U373 astrocytoma cells. Curr HIV Res 2005; 3: 277-288.
182. Vesce S, Bezzi P, Rossi D, Meldolesi J, Volterra A. HIV-1 gp120 glycoprotein affects the astrocyte control of extracellular glutamate by both inhibiting the uptake and stimulating the release of the amino acid. FEBS Lett 1997; 411: 107-109.
183. Wang Z, Pekarskaya O, Bencheikh M, et al. Reduced expression of glutamate transporter EAAT2 and impaired glutamate transport in human primary astrocytes exposed to HIV-1 or gp120. Virology 2003; 312: 60-73.
184. Johnson SW, North RA. Opioids excite dopamine neurons by hyperpolarization of local interneurons. J Neurosci 1992; 12: 483-488.
185. Gupta RG, Kelly KM, Helke KL, et al. HIV and SIV induce alterations in CNS CaMKII expression and activation: a potential mechanism for cognitive impairment. Am J Pathol 2010; 176: 2776-2784.
186. Paul S, Connor JA. NR2B-NMDA receptor-mediated increases in intracellular Ca2+ concentration regulate the tyrosine phosphatase, STEP, and ERK MAP kinase signaling. J Neurochem 2010; 114: 1107-1118.
187. Leveille F, El GF, Gouix E, et al. Neuronal viability is controlled by a functional relation between synaptic and extrasynaptic NMDA receptors. FASEB J 2008; 22: 4258-4271.
188. Leveille F, Papadia S, Fricker M, et al. Suppression of the intrinsic apoptosis pathway by synaptic activity. J Neurosci 2010; 30: 2623-2635.
189. Kerchner GA, Nicoll RA. Silent synapses and the emergence of a postsynaptic mechanism for LTP. Nat Rev Neurosci 2008; 9: 813-825.
190. Papadia S, Soriano FX, Leveille F, et al. Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses. Nat Neurosci 2008; 11: 476-487.
191. Soriano FX, Hardingham GE. Compartmentalized NMDA receptor signalling to survival and death. J Physiol 2007; 584: 381-387.
192. Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 2008; 7: 1091-1098.
193. Balazs R. Trophic effect of glutamate. Curr Top Med Chem 2006; 6: 961-968.
194. Hetman M, Kharebava G. Survival signaling pathways activated by NMDA receptors. Curr Top Med Chem 2006; 6: 787-799.
195. Sutton G, Chandler LJ. Activity-dependent NMDA receptormediated activation of protein kinase B/Akt in cortical neuronal cultures. J Neurochem 2002; 82: 1097-1105.
196. Friguls B, Petegnief V, Justicia C, Pallas M, Planas AM. Activation of ERK and Akt signaling in focal cerebral ischemia: modulation by TGF-alpha and involvement of NMDA receptor. Neurobiol Dis 2002; 11: 443-456.
197. Schmitt HP. Pouring oil into the fire? On the conundrum of the beneficial effects of NMDA receptor antagonists in Alzheimer disease. Psychopharmacology (Berl) 2005; 179: 151-153.
198. Gelman BB, Spencer JA, Holzer CE, III, Soukup VM. Abnormal striatal dopaminergic synapses in National NeuroAIDS Tissue Consortium subjects with HIV encephalitis. J Neuroimmune Pharmacol 2006; 1: 410-420.
199. Kumar AM, Ownby RL, Waldrop-Valverde D, Fernandez B, Kumar M. Human immunodeficiency virus infection in the CNS and decreased dopamine availability: relationship with neuropsychological performance. J Neurovirol 2011; 17: 26-40.
200. Ferris MJ, Frederick-Duus D, Fadel J, Mactutus CF, Booze RM. Hyperdopaminergic tone in HIV-1 protein treated rats and cocaine sensitization. J Neurochem 2010; 115: 885-896.
201. Ferris MJ, Mactutus CF, Booze RM. Neurotoxic profiles of HIV, psychostimulant drugs of abuse, and their concerted effect on the brain: current status of dopamine system vulnerability in NeuroAIDS. Neurosci Biobehav Rev 2008; 32: 883-909.
202. Scheller C, Sopper S, Jenuwein M, et al. Early impairment in dopaminergic neurotransmission in brains of SIV-infected rhesus monkeys due to microglia activation. J Neurochem 2005; 95: 377-387.
203. Marcario JK, Manaye KF, SantaCruz KS, Mouton PR, Berman NE, Cheney PD. Severe subcortical degeneration in macaques infected with neurovirulent simian immunodeficiency virus. J Neurovirol 2004; 10: 387-399.
204. Czub S, Czub M, Koutsilieri E, et al. Modulation of simian immunodeficiency virus neuropathology by dopaminergic drugs. Acta Neuropathol (Berl) 2004; 107: 216-226.
205. Czub S, Koutsilieri E, Sopper S, et al. Enhancement of central nervous system pathology in early simian immunodeficiency virus infection by dopaminergic drugs. Acta Neuropathol (Berl) 2001; 101: 85-91.
206. Theodore S, Cass WA, Maragos WF. Methamphetamine and human immunodeficiency virus protein Tat synergize to destroy dopaminergic terminals in the rat striatum. Neuroscience 2006; 137: 925-935.
207. Cass WA, Harned ME, Peters LE, Nath A, Maragos WF. HIV-1 protein Tat potentiation of methamphetamine-induced decreases in evoked overflow of dopamine in the striatum of the rat. Brain Res 2003; 984: 133-142.
208. Bagley EE, Hacker J, Chefer VI, et al. Drug-induced GABA transporter currents enhance GABA release to induce opioid withdrawal behaviors. Nat Neurosci 2011; 14: 1548-1554.
209. Jiang ZG, North RA. Pre- and postsynaptic inhibition by opioids in rat striatum. J Neurosci 1992; 12: 356-361.
210. Haughey NJ, Mattson MP. Calcium dysregulation and neuronal apoptosis by the HIV-1 proteins Tat and gp120. J Acquir Immune Defic Syndr 2002; 31 Suppl 2: S55-S61.
211. Khan MZ, Brandimarti R, Patel JP, et al. Apoptotic and antiapoptotic effects of CXCR4: is it a matter of intrinsic efficacy? Implications for HIV neuropathogenesis. AIDS Res Hum Retroviruses 2004; 20: 1063-1071.
212. Bachis A, Cruz MI, Mocchetti I. M-tropic HIV envelope protein gp120 exhibits a different neuropathological profile than T-tropic gp120 in rat striatum. Eur J Neurosci 2010; 32: 570-578.
213. El-Hage N, Dever SM, Fitting S, Ahmed T, Hauser KF. HIV-1 coinfection and morphine co-exposure severely dysregulate HCVinduced hepatic pro-inflammatory cytokine release and free radical production: increased pathogenesis coincides with uncoordinated host-defenses. J Virol 2011; 85: 11601-14.
214. Chen L, Liu J, Xu C, Keblesh J, Zang W, Xiong H. HIV-1gp120 nduces neuronal apoptosis through enhancement of 4- aminopyridine-senstive outward K currents. PLoS One 2011; 6: 25994.
215. Garden GA, Budd SL, Tsai E, et al. Caspase cascades in human mmunodeficiency virus-associated neurodegeneration. J Neurosci 2002; 22: 4015-40.
216. Bachis A, Biggio F, Major EO, Mocchetti I. M- and T-tropic HIVs romote apoptosis in rat neurons. J Neuroimmune Pharmacol 2009; 4: 150-160.
217. Peng F, Dhillon N, Callen S, et al. Platelet-derived growth factor protects neurons against gp120-mediated toxicity. J Neurovirol 2008; 14: 62-72.
218. Acquas E, Bachis A, Nosheny RL, Cernak I, Mocchetti I. Human immunodeficiency virus type 1 protein gp120 causes neuronal cell death in the rat brain by activating caspases. Neurotox Res 2004; 5: 605-615.
219. Bachis A, Major EO, Mocchetti I. Brain-derived neurotrophic factor inhibits human immunodeficiency virus-1/gp120-mediated cerebellar granule cell death by preventing gp120 internalization. J Neurosci 2003; 23: 5715-5722.
220. Lannuzel A, Barnier JV, Hery C, et al. Human immunodeficiency virus type 1 and its coat protein gp120 induce apoptosis and activate JNK and ERK mitogen-activated protein kinases in human neurons. Ann Neurol 1997; 42: 847-856.
221. Lazarini F, Casanova P, Tham TN, et al. Differential signalling of the chemokine receptor CXCR4 by stromal cell-derived factor 1 and the HIV glycoprotein in rat neurons and astrocytes. Eur J Neurosci 2000; 12: 117-125.
222. Meucci O, Fatatis A, Simen AA, Bushell TJ, Gray PW, Miller RJ. Chemokines regulate hippocampal neuronal signaling and gp120 neurotoxicity. Proc Natl Acad Sci USA 1998; 95: 14500-14505.
223. Medders KE, Sejbuk NE, Maung R, Desai MK, Kaul M. Activation of p38 MAPK is required in monocytic and neuronal cells for HIV glycoprotein 120-induced neurotoxicity. J Immunol 2010; 185: 4883-4895.
224. Bodner A, Toth PT, Miller RJ. Activation of c-Jun N-terminal kinase mediates gp120IIIB- and nucleoside analogue-induced sensory neuron toxicity. Exp Neurol 2004; 188: 246-253.
225. Xu H, Bae M, Tovar YRL, et al. The human immunodeficiency virus coat protein gp120 promotes forward trafficking and surface clustering of NMDA receptors in membrane microdomains. J Neurosci 2011; 31: 17074-17090.
226. Rogers TJ, Peterson PK. Opioid G protein-coupled receptors: signals at the crossroads of inflammation. Trends Immunol 2003; 24: 116-121.
227. Happel C, Steele AD, Finley MJ, Kutzler MA, Rogers TJ. DAMGO-induced expression of chemokines and chemokine receptors: the role of TGF-beta1. J Leukoc Biol 2008; 83: 956-963.
228. Patel JP, Sengupta R, Bardi G, Khan MZ, Mullen-Przeworski A, Meucci O. Modulation of neuronal CXCR4 by the micro-opioid agonist DAMGO. J Neurovirol 2006; 12: 492-500.
229. Burbassi S, Sengupta R, Meucci O. Alterations of CXCR4 function in mu-opioid receptor-deficient glia. Eur J Neurosci 2010; 32: 1278-1288.
230. Pitcher J, Shimizu S, Burbassi S, Meucci O. Disruption of neuronal CXCR4 function by opioids: preliminary evidence of ferritin heavy chain as a potential etiological agent in neuro AIDS. J Neuroimmunol 2010; 224: 66-71.
231. Abt AC, Meucci O. Regulation of neuronal ferritin heavy chain, a new player in opiate-induced chemokine dysfunction. J Neuroimmune Pharmacol 2011; 6: 466-476.
232. Sengupta R, Burbassi S, Shimizu S, et al. Morphine increases brain levels of ferritin heavy chain leading to inhibition of CXCR4- mediated survival signaling in neurons. J Neurosci 2009; 29: 2534-2544.
233. Todorich B, Zhang X, Connor JR. H-ferritin is the major source of iron for oligodendrocytes. Glia 2011; 59: 927-935.
234. Todorich B, Pasquini JM, Garcia CI, Paez PM, Connor JR. Oligodendrocytes and myelination: the role of iron. Glia 2009; 57: 467-478.
235. Connor JR, Menzies SL. Cellular management of iron in the brain. J Neurol Sci 1995; 134 Suppl: 33-44.
236. Kam AY, Liao D, Loh HH, Law PY. Morphine induces AMPA receptor internalization in primary hippocampal neurons via calcineurin-dependent dephosphorylation of GluR1 subunits. J Neurosci 2010; 30: 15304-15316.
237. Hauser KF, Mangoura D. Diversity of the endogenous opioid system in development: novel signal transduction translates multiple extracellular signals into neural cell growth and differentiation. Perspect Dev Neurobiol 1998; 5: 437-449.
238. Evans CJ. Diversity among the opioid receptors. In: Korenman SG, Barchas JD, editors. Biological Basis of Substance Abuse. 1 ed. New York: Oxford University Press 1993; p. 31-48.
239. Pan YX. Diversity and complexity of the mu opioid receptor gene: alternative pre-mRNA splicing and promoters. DNA Cell Biol 2005; 24: 736-750.
240. Ikeda H, Miyatake M, Koshikawa N, et al. Morphine modulation of thrombospondin levels in astrocytes and its implications for neurite outgrowth and synapse formation. J Biol Chem 2010; 285: 38415-38427.
241. Rusnati M, Taraboletti G, Urbinati C, et al. Thrombospondin- 1/HIV-1 tat protein interaction: modulation of the biological activity of extracellular Tat. Faseb J 2000; 14: 1917-1930.
242. Persidsky Y, Limoges J, Rasmussen J, Zheng J, Gearing A, Gendelman HE. Reduction in glial immunity and neuropathology by a PAF antagonist and an MMP and TNFalpha inhibitor in SCID mice with HIV-1 encephalitis. J Neuroimmunol 2001; 114: 57-68.
243. Koning N, Swaab DF, Hoek RM, Huitinga I. Distribution of the immune inhibitory molecules CD200 and CD200R in the normal central nervous system and multiple sclerosis lesions suggests neuron-glia and glia-glia interactions. J Neuropathol Exp Neurol 2009; 68: 159-167.
244. Kaul M, Lipton SA. Experimental and potential future therapeutic approaches for HIV-1 associated dementia targeting receptors for chemokines, glutamate and erythropoietin. Neurotox Res 2005; 8:167-186.
245. Nath A. Pathobiology of human immunodeficiency virus dementia. Semin Neurol 1999; 19: 113-127.
246. Gendelman HE, Persidsky Y, Ghorpade A, et al. The neuropathogenesis of the AIDS dementia complex. AIDS 1997; 11: 35-45.
247. Li W, Li G, Steiner J, Nath A. Role of Tat protein in HIV neuropathogenesis. Neurotox Res 2009; 16: 205-220.
248. Vallat-Decouvelaere AV, Chretien F, Gras G, Le Pavec G, Dormont D, Gray F. Expression of excitatory amino acid transporter-1 in brain macrophages and microglia of HIV-infected patients. A neuroprotective role for activated microglia? J Neuropathol Exp Neurol 2003; 62: 475-485.
249. Gras G, Chretien F, Vallat-Decouvelaere AV, et al. Regulated expression of sodium-dependent glutamate transporters and synthetase: a neuroprotective role for activated microglia and macrophages in HIV infection? Brain Pathol 2003; 13: 211-222.
250. Patton HK, Zhou ZH, Bubien JK, Benveniste EN, Benos DJ. Gp120-induced alterations of human astrocyte function: Na(+)/H(+) exchange, K(+) conductance, and glutamate flux. Am J Physiol Cell Physiol 2000; 279: C700-C708.
251. Gras G, Samah B, Hubert A, Leone C, Porcheray F, Rimaniol AC. EAAT expression by macrophages and microglia: still more questions than answers. Amino Acids 2012; 42: 221-229.
252. Gras G, Porcheray F, Samah B, Leone C. The glutamate-glutamine cycle as an inducible, protective face of macrophage activation. J Leukoc Biol 2006; 80: 1067-1075.
253. Chretien F, Vallat-Decouvelaere AV, Bossuet C, et al. Expression of excitatory amino acid transporter-2 (EAAT-2) and glutamine synthetase (GS) in brain macrophages and microglia of SIVmac251-infected macaques. Neuropathol Appl Neurobiol 2002; 28: 410-417.
254. Cali C, Bezzi P. CXCR4-mediated glutamate exocytosis from astrocytes. J Neuroimmunol 2010; 224: 13-21.
255. Haydon PG, Carmignoto G. Astrocyte control of synaptic transmission and neurovascular coupling. Physiol Rev 2006; 86: 1009-1031.
256. Ho VM, Lee JA, Martin KC. The cell biology of synaptic plasticity. Science 2011; 334: 623-628.
257. Araque A, Parpura V, Sanzgiri RP, Haydon PG. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci 1999; 22: 208-215.
258. Parpura V, Basarsky TA, Liu F, Jeftinija S, Haydon PG. Glutamate-mediated astrocyte-neuron signalling. Nature 1994; 369: 744-747.
259. Henneberger C, Papouin T, Oliet SH, Rusakov DA. Long-term potentiation depends on release of D-serine from astrocytes. Nature 2010; 463: 232-236.
260. Ozawa T, Nakagawa T, Shige K, Minami M, Satoh M. Changes in the expression of glial glutamate transporters in the rat brain accompanied with morphine dependence and naloxone-precipitated withdrawal. Brain Res 2001; 905: 254-258.
261. Mao J, Sung B, Ji RR, Lim G. Chronic morphine induces downregulation of spinal glutamate transporters: implications in morphine tolerance and abnormal pain sensitivity. J Neurosci 2002; 22: 8312-8623.
262. Becker Y. The spreading of HIV-1 infection in the human organism is caused by fractalkine trafficking of the infected lymphocytes--a review, hypothesis and implications for treatment. Virus Genes 2007; 34: 93-109.
263. Persidsky Y, Poluektova L. Immune privilege and HIV-1 persistence in the CNS. Immunol Rev 2006; 213: 180-194.
264. Schols D. HIV co-receptors as targets for antiviral therapy. Curr Top Med Chem 2004; 4: 883-893.
265. Glass WG, Rosenberg HF, Murphy PM. Chemokine regulation of inflammation during acute viral infection. Curr Opin Allergy Clin Immunol 2003; 3: 467-473.
266. Cotter R, Williams C, Ryan L, et al. Fractalkine (CX3CL1) and brain inflammation: Implications for HIV-1-associated dementia. J Neurovirol 2002; 8: 585-598.
267. Gabuzda D, Wang J. Chemokine receptors and mechanisms of cell death in HIV neuropathogenesis. J Neurovirol 2000; 6 Suppl 1: S24-S32.
268. Petito CK, Kerza-Kwiatecki AP, Gendelman HE, et al. Review: neuronal injury in HIV infection. J Neurovirol 1999; 5: 327-341.
269. Wesselingh SL, Thompson KA. Immunopathogenesis of HIVassociated dementia. Curr Opin Neurol 2001; 14: 375-379.
270. Lipton SA. Neuronal injury associated with HIV-1: approaches to treatment. Annu Rev Pharmacol Toxicol 1998; 38:159-77: 159-177.
271. Gendelman HE, Genis P, Jett M, Zhai QH, Nottet HS. An experimental model system for HIV-1-induced brain injury. Adv Neuroimmunol 1994; 4: 189-193.
272. Avdoshina V, Biggio F, Palchik G, Campbell LA, Mocchetti I. Morphine induces the release of CCL5 from astrocytes: potential neuroprotective mechanism against the HIV protein gp120. Glia 2010; 58: 1630-1639.
273. Erichsen D, Lopez AL, Peng H, et al. Neuronal injury regulates fractalkine: relevance for HIV-1 associated dementia. J Neuroimmunol 2003; 138: 144-155.
274. Tong N, Perry SW, Zhang Q, et al. Neuronal fractalkine expression in HIV-1 encephalitis: roles for macrophage recruitment and neuroprotection in the central nervous system. J Immunol 2000; 164: 1333-1339.
275. Meucci O, Fatatis A, Simen AA, Miller RJ. Expression of CX3CR1 chemokine receptors on neurons and their role in neuronal survival. Proc Natl Acad Sci USA 2000; 97: 8075-8080.
276. Combadiere C, Salzwedel K, Smith ED, Tiffany HL, Berger EA, Murphy PM. Identification of CX3CR1. A chemotactic receptor for the human CX3C chemokine fractalkine and a fusion coreceptor for HIV-1. J Biol Chem 1998; 273: 23799-23804.
277. Stiene-Martin A, Knapp PE, Martin KM, et al. Opioid system diversity in developing neurons, astroglia, and oligodendroglia in the subventricular zone and striatum: impact on gliogenesis in vivo. Glia 2001; 36: 78-88.
278. Stiene-Martin A, Hauser KF. Glial growth is regulated by agonists selective for multiple opioid receptor types in vitro. J Neurosci Res 1991; 29: 538-548.
279. Knapp PE, Itkis OS, Zhang L, Spruce BA, Bakalkin G, Hauser KF. Endogenous opioids and oligodendroglial function: possible autocrine/paracrine effects on cell survival and development. Glia 2001; 35: 156-165.
280. Spruce BA, Curtis R, Wilkin GP, Glover DM. A neuropeptide precursor in cerebellum: Proenkephalin exists in subpopulations of both neurons and astrocytes. EMBO J 1990; 9: 1787-1795.
281. Low KG, Allen RG, Melner MH. Differential regulation of proenkephalin expression in astrocytes by cytokines. Endocrinology 1992; 131: 1908-1914.
282. Melner MH, Low KG, Allen RG, Nielson CP, Young SL, Saneto RP. The regulation of proenkephalin expression in a distinct population of glial cells. EMBO J 1990; 9: 791-796.
283. Shinoda H, Marini AM, Cosi C, Schwartz JP. Brain region and gene specificity of neuropeptide gene expression in cultured astrocytes. Science 1989; 245: 415-417.
284. Ruzicka BB, Akil H. The interleukin-1beta-mediated regulation of proenkephalin and opioid receptor messenger RNA in primary astrocyte-enriched cultures. Neuroscience 1997; 79: 517-524.
285. McCarthy KD, Enkvist K, Shao Y. Astroglial adrenergic receptors: expression and function. In: Kettenmann H, Ransom BR, editors. Neuroglia. 1 ed. New York: Oxford Univ. Press 1995; p. 354-366.
286. Emsley JG, Macklis JD. Astroglial heterogeneity closely reflects the neuronal-defined anatomy of the adult murine CNS. Neuron Glia Biol 2006; 2: 175-186.
287. Zhang Y, Barres BA. Astrocyte heterogeneity: an underappreciated topic in neurobiology. Curr Opin Neurobiol 2010; 20: 588-594.
288. Shao Y, Porter JT, McCarthy KD. Neuroligand receptor heterogeneity among astroglia. Perspect Dev Neurobiol 1994; 2: 205-215.
289. Kimelberg HK. Receptors on astrocytes--what possible functions? Neurochem Int 1995; 26: 27-40.
290. Venance L, Premont J, Glowinski J, Giaume C. Gap junctional communication and pharmacological heterogeneity in astrocytes cultured from the rat striatum. J Physiol 1998; 510 (Pt 2): 429-440.
291. Bachoo RM, Kim RS, Ligon KL, et al. Molecular diversity of astrocytes with implications for neurological disorders. Proc Natl Acad Sci USA 2004; 101: 8384-8389.
292. Theodosis DT, Poulain DA, Oliet SH. Activity-dependent structural and functional plasticity of astrocyte-neuron interactions. Physiol Rev 2008; 88: 983-1008.
293. El-Hage N, Podhaizer EM, Sturgill J, Hauser KF. Toll-like receptor expression and activation in astroglia: differential regulation by HIV-1 Tat, gp120, and morphine. Immunol Invest 2011; 40: 498-522.
294. Wang J, Barke RA, Charboneau R, Roy S. Morphine impairs host innate immune response and increases susceptibility to Streptococcus pneumoniae lung infection. J Immunol 2005; 174: 426-434.
295. Li Y, Li H, Zhang Y, et al. Toll-like receptor 2 is required for opioids-induced neuronal apoptosis. Biochem Biophys Res Commun 2010; 391: 426-430.
296. Hutchinson MR, Lewis SS, Coats BD, et al. Possible involvement of toll-like receptor 4/myeloid differentiation factor-2 activity of opioid inactive isomers causes spinal proinflammation and related behavioral consequences. Neuroscience 2010; 167: 880-893.
297. Hutchinson MR, Zhang Y, Shridhar M, et al. Evidence that opioids may have toll-like receptor 4 and MD-2 effects. Brain Behav Immun 2010; 24: 83-95.
298. Karadottir R, Cavelier P, Bergersen LH, Attwell D. NMDA receptors are expressed in oligodendrocytes and activated in ischaemia. Nature 2005; 438: 1162-1166.
299. Micu I, Jiang Q, Coderre E, et al. NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia. Nature 2006; 439: 988-992.
300. Salter MG, Fern R. NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury. Nature 2005; 438: 1167-1171.
301. Knapp PE, Maderspach K, Hauser KF. Endogenous opioid system in developing normal and jimpy oligodendrocytes: μ and κ opioid receptors mediate differential mitogenic and growth responses. Glia 1998; 22: 189-201.
302. Hahn JW, Jagwani S, Kim E, et al. Mu and kappa opioids modulate mouse embryonic stem cell-derived neural progenitor differentiation via MAP kinases. J Neurochem 2010; 112: 1431-1441.
303. Sanchez ES, Bigbee JW, Fobbs W, Robinson SE, Sato-Bigbee C. Opioid addiction and pregnancy: perinatal exposure to buprenorphine affects myelination in the developing brain. Glia 2008; 56: 1017-1027.
304. Knapp PE, Adjan VV, Hauser KF. Cell-specific loss of κ opioid receptors in oligodendrocytes of the dysmyelinating jimpy mouse. Neurosci Lett 2009; 451: 114-118.
305. Tryoen-Toth P, Gaveriaux-Ruff C, Labourdette G. Downregulation of mu-opioid receptor expression in rat oligodendrocytes during their development in vitro. J Neurosci Res 2000; 60: 10-20.
306. Chomiak T, Hu B. What is the optimal value of the g-ratio for myelinated fibers in the rat CNS? A theoretical approach. PLoS One 2009; 4: e7754.
307. Berman JW, Carson MJ, Chang L, et al. NeuroAIDS, drug abuse, and inflammation: building collaborative research activities. J Neuroimmune Pharmacol 2006; 1: 351-399.