Selective monoaminergic and histaminergic circuit dysregulation following long-term HIV-1 protein exposure

  • Adam R. Denton
  • Srimal A. Samaranayake
  • Kristin N. Kirchner
  • Robert F. RoscoeJr
  • Shane N. Berger
  • Steven B. Harrod
  • Charles F. Mactutus
  • Parastoo Hashemi
  • Rosemarie M. BoozeEmail author


Between 30 and 60% of HIV-seropositive individuals develop symptoms of clinical depression and/or apathy. Dopamine and serotonin are associated with motivational alterations; however, histamine is less well studied. In the present study, we used fast-scan cyclic voltammetry in HIV-1 transgenic (Tg) rats to simultaneously analyze the kinetics of nucleus accumbens dopamine (DA), prefrontal cortical serotonin (5-HT), and hypothalamic histamine (HA). For voltammetry, subjects were 15 HIV-1 Tg (7 male, 8 female) and 20 F344/N (11 male, 9 female) adult rats. Both serotonergic and dopaminergic release and reuptake kinetics were decreased in HIV-1 Tg animals relative to controls. In contrast, rates of histamine release and reuptake increased in HIV-1 Tg rats. Additionally, we used immunohistochemical (IHC) methods to identify histaminergic neurons in the tuberomammillary nucleus (TMN) of the hypothalamus. For IHC, subjects were 9 HIV-1 Tg (5 male, 4 female) and 9 F344/N (5 male, 4 female) adult rats. Although the total number of TMN histaminergic cells did not differ between HIV-1 Tg rats and F344/N controls, a significant sex effect was found, with females having an increased number of histaminergic neurons, relative to males. Collectively, these findings illustrate neurochemical alterations that potentially underlie or exacerbate the pathogenesis of clinical depression and/or apathy in HIV-1.


HIV-1 Nucleus accumbens Fast-scan cyclic voltammetry Dopamine Serotonin Histamine immunohistochemistry 



The authors acknowledge and thank Dr. Michael Cranston and Dr. Hailong Li for their assistance with this project.

Funding information

This research was supported by the National Institute of Health Grants NS100624, DA013137, HD043680, MH106392 & by a National Institute of Health T32 Training Grant 5T32GM081740.

Compliance with ethical standards

This experiment was conducted in accordance with the recommendations of the National Institute of Health’s Guide for the Care and Use of Laboratory Animals. Research protocols used were approved by the University of South Carolina Institutional Animal Care and Use Committee (assurance number: D16-00028). Additionally, the authors report no conflicts of interest or competing financial interests.


  1. Aksenov MY, Aksenova MV, Silvers JM, Mactutus CF, Booze RM (2008) Different effects of selective dopamine uptake inhibitors GBR 12909 and WIN 35428 on HIV-1 Tat toxicity in rat fetal midbrain neurons. Neurotoxicology 29:971–977Google Scholar
  2. Becker JB (2016) Sex differences in addiction. Dialogues Clin Neurosci 18:395–402Google Scholar
  3. Becker JB, McClellan M, Reed BG (2016) Sociocultural context for sex differences in addiction. Addict Biol 21:1052–1059Google Scholar
  4. Bertrand SJ, Aksenova MV, Mactutus CF, Booze RM (2013) HIV-1 Tat protein variants: critical role for the cysteine region in synaptodendritic injury. Exp Neurol 248:228–235Google Scholar
  5. Bertrand SJ, Mactutus CF, Harrod SB, Moran LM, Booze RM (2018) HIV-1 proteins dysregulate motivational processes and dopamine circuitry. Sci Rep 8:7869. Google Scholar
  6. Bhatia MS, Munjal S (2014) Prevalence of depression in people living with HIV/AIDS undergoing ART and factors associated with it. J Clin Diagn Res 8:WC01–WC04Google Scholar
  7. Blandina P, Munari L, Provensi G, Passani MB (2012) Histamine neurons in the tuberomamillary nucleus: a whole center or distinct subpopulations? Front Syst Neurosci 6:33. Google Scholar
  8. Booze RM, Wood ML, Welch MA, Berry S, Mactutus CF (1999) Estrous cyclicity and behavioral sensitization in female rats following repeated intravenous cocaine administration. Pharmacol Biochem Behav 64:605–610Google Scholar
  9. Brown RE, Stevens DR, Haas HL (2001) The physiology of brain histamine. Prog Neurobiol 63:637–672Google Scholar
  10. Bryant VE, Whitehead NE, Burrell LE, Dotson VM, Cook RL, Malloy P, Devlin K, Cohen RA (2015) Depression and apathy among people living with HIV: implications for treatment of HIV associated neurocognitive disorders. AIDS Behav 19:1430–1437Google Scholar
  11. Castellon SA, Hinkin CH, Wood S, Yarema KT (1998) Apathy, depression, and cognitive performance in HIV-1 infection. J Neuropsychol 10:320–328Google Scholar
  12. Caudle WM, Richardson JR, Wang MZ, Taylor TN, Guillot TS, McCormack AL, [ … ] Millar G.W. (2007) Reduced vesicular storage of dopamine causes progressive nigrostriatal neurodegeneration. J Neurosci 27:8138–8148Google Scholar
  13. Chang L, Wang GJ, Volkow ND, Ernst T, Telang F, Logan J, Fowler JS (2008) Decreased brain dopamine transporters are related to cognitive deficits in HIV patients with or without cocaine abuse. Neuroimage 42:869–878Google Scholar
  14. Eiden LE, Weihe E (2011) VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse. Ann N Y Acad Sci 216:86–98Google Scholar
  15. Ericson H, Watanabe T, Köhler C (1987) Morphological analysis of the tuberomammillary nucleus in the rat brain: delineation of subgroups with antibody against L-histidine decarboxylase as a marker. J Comp Neurol 263:1–24Google Scholar
  16. Ericson H, Blomqvist A, Köhler C (1989) Brainstem afferents to the tuberomammillary nucleus in the rat brain with special reference to monoaminergic innervation. J Comp Neurol 281:169–192Google Scholar
  17. Eshun-Wilson L, Siegfried N, Akena DH, Stein DJ, Obuku EA, Joska JA (2018) Antidepressants for depression in adults with HIV infection. Cochrane Database Syst Rev 1:CD008525. Google Scholar
  18. Ferris MJ, Mactutus CF, Booze RM (2008) 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 32:883–909Google Scholar
  19. Ferris MJ, Frederick-Duus D, Fadel J, Mactutus CF, Booze RM (2009a) The human immunodeficiency virus-1-associated protein TAT1-86 impairs dopamine transporters and interacts with cocaine to reduce nerve terminal function: a no-net-flux microdialysis study. Neurosci 10:1292–1299Google Scholar
  20. Ferris MJ, Frederick-Duus D, Fadel J, Mactutus CF, Booze RM (2009b) In vivo microdialysis in awake, freely moving rats demonstrates HIV-1 tat-induced alterations in dopamine transmission. Synapse 63:181–185Google Scholar
  21. Fitting S, Booze RM, Hasselrot U, Mactutus CF (2008) Differential long-term neurotoxicity of HIV-1 proteins in the rat hippocampal formation: a design-based stereological study. Hippocampus 18:135–147Google Scholar
  22. Fitting S, Booze RM, Mactutus CF (2015) HIV-1 proteins, Tat and gp120, target the developing dopamine system. Curr HIV Res 13:21–42Google Scholar
  23. Fletcher PJ, Selhi ZF, Azampanah A, Sills TL (2001) Reduced brain serotonin activity disrupts prepulse inhibition of the acoustic startle reflex. Effects of 5,7-dihydroxytryptamine and p-chlorophenyalanine. Neuropsychopharmacology 24:399–409Google Scholar
  24. Haas H, Panula P (2003) The role of histamine and the tuberomamillary nucleus in the nervous system. Nat Rev Neurosci 4:121–130Google Scholar
  25. Hashemi P, Dankoski EC, Petrovi J, Keithley RB, Wightman RM (2009) Voltammetric detection of 5-hydroxytryptamine release in the rat brain. Anal Chem 81:9462–9471Google Scholar
  26. Hestad KA, Menon JA, Silalukey-Ngoma M, Franklin DR, Imasuku ML, Kalima K, Heaton RK (2012) Sex differences in neuropsychological performance as an effect of human immunodeficiency virus infection. J Nerv Ment Dis 200:336–342. Google Scholar
  27. Javadi-Paydar M, Roscoe RF, Denton AR, Mactutus CF, Booze RM (2017) HIV-1 and cocaine disrupt dopamine reuptake and medium spiny neurons in female rat striatum. 12: e0188404 Doi:
  28. Kamat R, Woods SP, Marcotte TD, Ellis RJ, Grant I (2012) Implications of apathy for everyday functioning outcomes in persons living with HIV infection. Arch Clin Neuropsychol 27:520–531Google Scholar
  29. Kumar AM, Ownby RL, Waldrop-Valverde D, Fernandez B, Kumar M (2011) Human immunodeficiency virus infection in the CNS and decreased dopamine availability: relationship with neuropsychological performance. J Neuro-Oncol 17:26–40Google Scholar
  30. Maki PM, Rubin LH, Springer G, Seaberg EC, Sacktor N, Miller EN, Valcour V, Young MA, Becker JT, Martin EM (2018) Differences in cognitive function between women and men with HIV. J Acquir Immune Defic Syndr 79:101–107Google Scholar
  31. Marin RS, Firinciogullari S, Biedrzycki RC (1993) The sources of convergence between measures of apathy and depression. J Affect Discord 28:117–124Google Scholar
  32. Marquine MJ, Ludicello JE, Morgan EE, Brown GG, Letendre SL, Ellis RJ, [ … ] Heaton RK (2014) Frontal systems behaviors in comorbid human immunodeficiency virus infection and methamphetamine dependency. Psychiatry Res 215:208–216Google Scholar
  33. McIntosh RC, Rosselli M, Uddin L, Antoni M (2015) Neuropathological sequelae of human immunodeficiency virus and apathy: a review of neuropsychological and neuroimaging studies. Neurosci Biobehav Rev 55:47–164Google Scholar
  34. McLaurin KA, Booze RM, Mactutus CF (2016) Progression of temporal processing deficits in the HIV-1 transgenic rat. Sci Rep 6:32831. Google Scholar
  35. McLaurin KA, Booze RM, Mactutus CF (2017a) Evolution of the HIV-1 transgenic rat: utility in assessing the progression of HIV-1 associated neurocognitive disorders. J Neuro-Oncol 24:229–245Google Scholar
  36. McLaurin KA, Booze RM, Mactutus CF, Fairchild AJ (2017b) Sex matters: robust sex differences in signal detection in the HIV-1 transgenic rat. Front Behav Neurosci 11.
  37. McLaurin KA, Cook AK, Li H, League AF, Mactutus CF, Booze RM (2018a) Synaptic connectivity in medium spiny neurons of the nucleus accumbens: a sex-dependent mechanism underlying apathy in the HIV-1 transgenic rat. Front Behav Neurosci 12:285.
  38. McLaurin KA, Li H, Booze RM, Mactutus CF (2018b) Disruption of timing: NeuroHIV progression in the post-cART era. Sci Rep 9:827Google Scholar
  39. Midde NA, Gomez AM, Zhu J (2012) HIV-1 Tat protein decreases dopamine transporter cell surface expression and vesicular monoamine transporter-2 function in rat striatal synaptosomes. J NeuroImmune Pharmacol 7:629–639Google Scholar
  40. Nath A, Anderson C, Jones M, Maragos W, Booze R, Mactutus CF, Bell J, Hauser KF, Mattson M (2000) Neurotoxicity and dysfunction of dopaminergic systems associated with AIDS dementia. J Psychopharmacol 14:222–227Google Scholar
  41. Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM (2002) Neurobiology of depression. Neuron 34:13–25Google Scholar
  42. Owens MJ, Nemeroff CB (1994) Role of the serotonin in the pathophysiology of depression: focus on the serotonin transporter. Clin Chem 40:288–295Google Scholar
  43. Panula P, Yang HY, Costa E (1984) Histamine-containing neurons in the rat hypothalamus. Proc Natl Acad Sci U S A 81:2572–2576Google Scholar
  44. Paxinos G, Watson C (2014) The rat brain in stereotaxic coordinates. Academic Press, ElsevierGoogle Scholar
  45. Purohit V, Rapaka R, Shurtleff D (2011) Drugs of abuse, dopamine, and HIV-associated neurocognitive disorders/HIV-associated dementia. Mol Neurobiol 44:102–110Google Scholar
  46. Reid W, Sadowska M, Denaro F, Rao S, Foulke J, Hayes N (, Jones O, Doodnauth D, Davis H, Sill A, O’Driscoll P, Huso D, Fouts T, Lewis G, Hill M, Kamin-Lewis R, Wei C, Ray P, Gallo RC, Reitz M ) Bryant J (2001) An HIV-1 transgenic rat that develops HIV-related pathology and immunologic dysfunction. Proc Natl Acad Sci U S A 98:9271–9276Google Scholar
  47. Roscoe R, Mactutus CF, Booze RM (2014) HIV-1 transgenic female rat: synaptodendritic alterations of medium spiny neurons in the nucleus accumbens. J NeuroImmune Pharmacol 9:642–653Google Scholar
  48. Rowson SA, Harrell CS, Bekhbat M, Gangavelli A, Wu MJ, Kelly SD, Reddy R, Neigh GN (2016) Neuroinflammation and behavior in HIV-1 transgenic rats exposed to chronic adolescent stress. Front Psychiatry 7.
  49. Royal W, Cherner M, Burdo TH, Umlauf A, Letendre SL, Jumare J, [, Abimiku A’, Alabi P, Alkali N, Bwala S, Okwuasaba K, Eyzaguirre LM, Akolo C, Guo M, Williams KC ] Blattner WA (2016) Associations between cognition, gender and monocyte activation among HIV infected individuals in Nigeria. P One 11:2 e0147182 doi: Google Scholar
  50. Samaranayake S, Abdalla A, Robke R, Wood KM, Zeqja A, Hashemi P (2015) In vivo histamine voltammetry in the mouse premammillary nucleus. Analyst 140:3759–3765Google Scholar
  51. Samaranayake S, Abdalla A, Robke R, Nijhout HF, Reed MC, Best J, Hashemi P (2016) A voltammetric and mathematical analysis of histaminergic modulation of serotonin in the mouse hypothalamus. J Neurochem 138:374–383Google Scholar
  52. Silvers JM, Aksenov MY, Akensova MV, Beckly J, Olton P, Mactutus CF, Booze RM (2006) Dopaminergic marker proteins in the substantia nigra of human immunodeficiency virus type 1-infected brains. J Neuro-Oncol 12:40–145Google Scholar
  53. Sinharay S, Lee D, Shah S, Muthusamy S, Papadakis GZ, Ahang X, Maric D, Reid WC, Hammound DA (2017) Cross-sectional and longitudinal small animal PET shows pre and post-synaptic striatal dopaminergic deficits in an animal model of HIV. J Nucl Med 55:27–33Google Scholar
  54. Threlfell S, Cragg SJ, Kalio I, Turi GF, Coen CW, Greenfield SA (2004) Histamine H3 receptors inhibit serotonin release in substantia nigra pars reticulate. J Neurosci 24:8704–8710Google Scholar
  55. Torrealba F, Riberos ME, Contreras M, Valdes JL (2012) Histamine and motivation. Front Syst Neurosci 6:51. Google Scholar
  56. US Department of Veterans Affairs (2009) Primary care of veterans with HIV. Available from
  57. Vigorito M, Connaghan KP, Chang SL (2015) The HIV-1 transgenic rat model of neuroHIV. Brain Behav Immun 48:336–349Google Scholar
  58. Wada H, Inagaki N, Yamatodani A, Watanabe T (1991) Is the histaminergic neuron system a regulatory center for whole-brain activity? Trends Neurosci 14:415–418Google Scholar
  59. Watanabe T, Taguchi Y, Hayashi H, Tanaka J, Shiosaka S, Tohyama M, Kubota H, Terano Y, Wada H (1983) Evidence for the presence of a histaminergic neuron system in the rat brain: an immunohistochemical analysis. Neurosci Lett 39:249–254Google Scholar
  60. Waynforth HB, Flecknell PA (1992) Experimental and surgical techniques in the rat. Elsevier Science, New YorkGoogle Scholar
  61. West MJ (2012) Basic stereology for biologists and neuroscientists. Cold Spring Harbor Laboratory PressGoogle Scholar
  62. Westwood FR (2008) The female rat reproductive cycle: a practical histological guide to staging. Toxicol Pathol 36:375–384Google Scholar
  63. World Health Organization (2017). HIV/AIDS global health observatory data. Available from
  64. Zhu J, Mactutus CF, Wallace DR, Booze R (2009) HIV-1 Tat-protein-induced rapid and reversible decrease in [3H] dopamine uptake: dissociation of [3H] dopamine uptake and [3H]2β-carbomethoxy-3-β-(4-fluorophenyl) tropane (WIN35,428) binding in rat striatal synaptosomes. J Pharmacol Exp Ther 329:1071–1083Google Scholar
  65. Zhu J, Midde NM, Gomez AM, Sun WL, Quizon PM, Zhan CG (2016) HIV-1 transgenic rats display an increase in [3H] dopamine uptake in the prefrontal cortex and striatum. J Neurovirol 22:282–292Google Scholar

Copyright information

© Journal of NeuroVirology, Inc. 2019

Authors and Affiliations

  • Adam R. Denton
    • 1
  • Srimal A. Samaranayake
    • 2
  • Kristin N. Kirchner
    • 1
  • Robert F. RoscoeJr
    • 1
  • Shane N. Berger
    • 2
  • Steven B. Harrod
    • 1
  • Charles F. Mactutus
    • 1
  • Parastoo Hashemi
    • 2
  • Rosemarie M. Booze
    • 1
    Email author
  1. 1.Behavioral Neuroscience Laboratory, Department of PsychologyUniversity of South CarolinaColumbiaUSA
  2. 2.Department of ChemistryUniversity of South CarolinaColumbiaUSA

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