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Neurometabolite Abnormalities in Simian Immunodeficiency Virus-Infected Macaques with Chronic Morphine Administration

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Abstract

Opiate abuse increases the risk for human immunodeficiency virus (HIV) infection, while both opiates and HIV may impact the immune and nervous systems. To model potential interactions between opiate drugs and HIV on the brain, neurometabolite levels were evaluated in simian immunodeficiency virus (SIV)-infected macaques with or without chronic morphine administration. Over the course of the study, 58% of these SIV-infected animals progressed to acquired immune deficiency syndrome (AIDS). Brain extracts from four brain regions were evaluated with proton magnetic resonance spectroscopy. Animals with AIDS had lower N-acetyl-aspartate in all four brain regions (p ≤ 0.05) as well as lower frontal gray matter total creatine (p = 0.03), lower frontal white matter (p = 0.003) and caudate (p = 0.002) glutamate, and higher frontal white matter myo-inositol (p = 0.05) than the healthier non-AIDS macaques. Morphine-dependent animals had higher levels of myo-inositol in the putamen (p = 0.003), especially those with AIDS. In the animals with AIDS, those with morphine dependence had higher total creatine in the frontal white matter (p = 0.04) than those treated with saline, which in turn had lower creatine than saline-injected animals without AIDS (p = 0.04), leading to an interaction between the effects of morphine and AIDS on total creatine in this brain region (ANOVA p = 0.02). The majority of these brain metabolites correlated with viral counts indicating more severe metabolite abnormalities in animals with higher viral loads or set points. Collectively, these findings suggest that chronic morphine may protect against the neurotoxic effect of AIDS and reinforce the importance of maintaining a low viral load in AIDS.

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References

  • Barker PB, Lee RR, McArthur JC (1995) AIDS dementia complex: evaluation with proton MR spectroscopic imaging. Radiology 195:58–64

    PubMed  CAS  Google Scholar 

  • Bartlett E, Mikulis DJ (2005) Chasing “chasing the dragon” with MRI: leukoencephalopathy in drug abuse. Br J Radiol 78:997–1004

    Article  PubMed  CAS  Google Scholar 

  • Beard E, Braissant O (2010) Synthesis and transport of creatine in the CNS: importance for cerebral functions. J Neurochem [Epub ahead of print]

  • CDC CfDCaP (2002) Drug-associated HIV transmission continues in the United States. Centers, fDCaP. Rockville MD, CDC. Fact Sheet

  • Chang L, Ernst T, Leonido-Yee M, Walot I, Singer E (1999) Cerebral metabolite abnormalities correlate with clinical severity of HIV-1 cognitive motor complex. Neurology 52:100–108

    PubMed  CAS  Google Scholar 

  • Chang L, Ernst T, Witt M, Ames N, Jocivich J, Speck O, Gaiefsky M, Walot I, Miller E (2002) Relationships among cerebral metabolites, cognitive function and viral loads in antiretroviral-naïve HIV patients. Neuroimage 17:1638–1648

    Article  PubMed  Google Scholar 

  • Chang L, Lee PL, Yiannoutsos CT, Ernst T, Marra CM, Richards T, Kolson D, Schifitto G, Jarvik JG, Miller EN, Lenkinski R, Gonzalez G, Navia BA (2004) A multicenter in vivo proton-MRS study of HIV-associated dementia and its relationship to age. Neuroimage 23:1336–1347

    Article  PubMed  CAS  Google Scholar 

  • Chang L, Ernst T, Speck O, Grob CS (2005) Additive effects of HIV and chronic methamphetamine use on brain metabolite abnormalities. Am J Psychiatry 162(2):361–9

    Google Scholar 

  • Chang L, Cloak C, Yakupov R, Ernst T (2006) Combined and independent effects of chronic marijuana use and HIV on brain metabolites. J Neuroimmune Pharmacol 1(1):65–76

    Google Scholar 

  • Donahoe RM, Vlahov D (1998) Opiates as potential cofactors in progression of HIV-1 infections to AIDS. J Neuroimmunol 83:77–87

    Article  PubMed  CAS  Google Scholar 

  • Donahoe RM, O’Neil SP, Marsteller FA, Novembre FJ, Anderson DC, Lankford-Turner P, McClure HH (2009) Probable deceleration of progression of Simian AIDS affected by opiate dependency: studies with a rhesus macaque/SIVsmm9 model. J Acquir Immune Defic Syndr 50:241–249

    Article  PubMed  Google Scholar 

  • Everall IP (2004) Interaction between HIV and intravenous heroin abuse? J Neuroimmunol 147:13–15

    Article  PubMed  CAS  Google Scholar 

  • Fuller RA, Westmoreland SV, Ratai E, Greco JB, Kim JP, Lentz MR, He J, Sehgal PK, Masliah E, Halpern E, Lackner AA, Gonzalez RG (2004) A prospective longitudinal in vivo 1H MR spectroscopy study of the SIV/macaque model of neuroAIDS. BMC Neurosci 5:10

    Article  PubMed  Google Scholar 

  • Fultz PN, McClure HM, Anderson DC, Swenson RB, Anand R, Srinivasan A (1986) Isolation of a T-lymphotropic retrovirus from naturally infected sooty mangabey monkeys (Cercocebus atys). Proc Natl Acad Sci 83:5286–5290

    Article  PubMed  CAS  Google Scholar 

  • González RG, Cheng LL, Westmoreland SV, Sakaie KE, Becerra LR, Lee PL, Masliah E, Lackner AA (2000) Early brain injury in the SIV-macaque model of AIDS. AIDS 14(18):2841–9

    Google Scholar 

  • Greco JB, Westmoreland SV, Ratai EM, Lentz MR, Sakaie K, He J, Sehgal PK, Masliah E, Lackner AA, Gonzalez RG (2004) In vivo 1H MRS of brain injury and repair during acute SIV infection in the macaque model of neuroAIDS. Magn Reson Med 51:1108–1114

    Article  PubMed  CAS  Google Scholar 

  • Haselhorst R, Dursteler-MacFarland KM, Scheffler K, Ladewig D, Muller-Spahn F, Stohler R, Seelig J, Seifritz E (2002) Frontocortical N-acetylaspartate reduction associated with long-term i.v. heroin use. Neurology 58:305–307

    PubMed  CAS  Google Scholar 

  • Kim JP, Lentz MR, Westmoreland SV, Greco JB, Ratai EM, Halpern E, Lackner AA, Masliah E, Gonzalez RG (2005) Relationships between astrogliosis and 1H MR spectroscopic measures of brain choline/creatine and myo-inositol/creatine in a primate model. AJNR 26:752–759

    PubMed  Google Scholar 

  • Lentz MR, Lee V, Westmoreland SV, Ratai EM, Halpern EF, Gonzalez RG (2008a) Factor analysis reveals differences in brain metabolism in macaques with SIV/AIDS and those with SIV-induced encephalitis. NMR Biomed 21:878–887

    Article  PubMed  CAS  Google Scholar 

  • Lentz MR, Westmoreland SV, Lee V, Ratai EM, Halpern EF, Gonzalez RG (2008b) Metabolic markers of neuronal injury correlate with SIV CNS disease severity and inoculum in the macaque model of neuroAIDS. Magn Reson Med 59:475–484

    Article  PubMed  CAS  Google Scholar 

  • McClure HM, Anderson DC, Ansari AA, Fultz PN, Klumpp SA, Schinazi RF (1990) Nonhuman primate models for evaluation of AIDS therapy. Ann NY Acad Sci 616:287–298

    Article  PubMed  CAS  Google Scholar 

  • Meyerhoff D, Bloomer C, Cardenas V, Norman D, Weiner M, Fein G (1999) Elevated subcortical choline metabolites in cognitively and clinically asymptomatic HIV+ patients. Neurology 52:995–1003

    PubMed  CAS  Google Scholar 

  • Offiah C, Hall E (2008) Heroin-induced leukoencephalopathy: characterization using MRI, diffusion-weighted imaging, and MR spectroscopy. Clin Radiol 63:146–152

    Article  PubMed  CAS  Google Scholar 

  • Peterson PK, Sharp BM, Gekker G, Portoghese PS, Sannerud K, Balfour HH Jr (1990) Morphine promotes the growth of HIV-1 in human peripheral blood mononuclear cell cocultures. AIDS 4:869–873

    Article  PubMed  CAS  Google Scholar 

  • Pfefferbaum A, Adalsteinsson E, Sullivan EV (2005) Cortical NAA deficits in HIV infection without dementia: influence of alcoholism comorbidity. Neuropsychopharmacology 30:1392–1399

    Article  PubMed  CAS  Google Scholar 

  • Ratai EM, Pilkenton SJ, Greco JB, Lentz MR, Bombardier JP, Turk KW, He J, Joo CG, Lee V, Westmoreland S, Halpern E, Lackner AA, Gonzalez RG (2009) In vivo proton magnetic resonance spectroscopy reveals region specific metabolic responses to SIV infection in the macaque brain. BMC Neurosci 10:63

    Article  PubMed  Google Scholar 

  • Sokol M, Przybyszewski WM, Matlas B (2004) Investigation of metabolic changes in irradiated rat brain tissue by means of 1H NMR in vitro relaxation study. Solid State Nucl Magn Reson 25:53–60

    Article  PubMed  CAS  Google Scholar 

  • Tachikawa M, Fukaya M, Terasaki T, Ohtsuki S, Watanabe M (2004) Distinct cellular expressions of creatine synthetic enzyme GAMT and creatine kinases uCK-Mi and CK-B suggest a novel neuron–glial relationship for brain energy homeostasis. Eur J Neurosci 20:144–160

    Article  PubMed  Google Scholar 

  • Wallimann T (2007) Introduction—creatine: cheap ergogenic supplement with great potential for health and disease. Subcell Biochem 46:1–16

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank the Clinical Vet Staff at Yerkes National Primate Research Center. This study was supported by the National Institute on Drug Abuse (1K01-DA021203, R01-DA010440, 2K24-DA16170; 1K02-DA16991) and the National Center for Research Resources to the Yerkes National Primate Research Center (RR000165) and the New England Primate Research Center (RR000168).

Conflicts of interest

The authors have no conflicts of interest to disclose.

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Authors and Affiliations

  1. Department of Medicine, Neuroscience and MRI Research, University of Hawaii, 1356 Lusitana St #713, Honolulu, HI, 96813, USA

    Christine C. Cloak, Linda Chang & Thomas M. Ernst

  2. Harvard Medical School, Southborough, MA, USA

    Shawn P. O’Neil

  3. Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA

    Daniel C. Anderson

  4. Department of Pathology, School of Medicine, University of Utah, Salt Lake City, UT, USA

    Robert M. Donahoe

Authors
  1. Christine C. Cloak
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  2. Linda Chang
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  3. Shawn P. O’Neil
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  4. Thomas M. Ernst
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  5. Daniel C. Anderson
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  6. Robert M. Donahoe
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Corresponding author

Correspondence to Christine C. Cloak.

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Guarantors of the work: Christine C. Cloak, Linda Chang, and Robert M. Donahoe

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Cloak, C.C., Chang, L., O’Neil, S.P. et al. Neurometabolite Abnormalities in Simian Immunodeficiency Virus-Infected Macaques with Chronic Morphine Administration. J Neuroimmune Pharmacol 6, 371–380 (2011). https://doi.org/10.1007/s11481-010-9246-3

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  • DOI: https://doi.org/10.1007/s11481-010-9246-3

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