Brain Reward Function after Chronic and Binge Methamphetamine Regimens in Mice Expressing the HIV-1 TAT Protein

Author(s): James P. Kesby*, Ariel Chang, Julia A. Najera, Maria Cecilia G. Marcondes, Svetlana Semenova

Journal Name: Current HIV Research

Volume 17 , Issue 2 , 2019

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Graphical Abstract:


Background: Methamphetamine abuse and human immunodeficiency virus (HIV) are common comorbidities. HIV-associated proteins, such as the regulatory protein TAT, may contribute to brain reward dysfunction, inducing an altered sensitivity to methamphetamine reward and/or withdrawal in this population.

Objective: These studies examined the combined effects of TAT protein expression and, chronic and binge methamphetamine regimens on brain reward function.

Methods: Transgenic mice with inducible brain expression of the TAT protein were exposed to either saline, a chronic, or a binge methamphetamine regimen. TAT expression was induced via doxycycline treatment during the last week of methamphetamine exposure. Brain reward function was assessed daily throughout the regimens, using the intracranial self-stimulation procedure, and after a subsequent acute methamphetamine challenge.

Results: Both methamphetamine regimens induced withdrawal-related decreases in reward function. TAT expression substantially, but not significantly increased the withdrawal associated with exposure to the binge regimen compared to the chronic regimen, but did not alter the response to acute methamphetamine challenge. TAT expression also led to persistent changes in adenosine 2B receptor expression in the caudate putamen, regardless of methamphetamine exposure. These results suggest that TAT expression may differentially affect brain reward function, dependent on the pattern of methamphetamine exposure.

Conclusion: The subtle effects observed in these studies highlight that longer-term TAT expression, or its induction at earlier stages of methamphetamine exposure, may be more consequential at inducing behavioral and neurochemical effects.

Keywords: Adenosine receptor, animal model, dopamine, TAT protein, behavior, self-stimulation.

Soontornniyomkij V, Kesby JP, Morgan EE, et al. Effects of HIV and methamphetamine on brain and behavior: evidence from human studies and animal models. J Neuroimmune Pharmacol 2016; 11(3): 495-510.
[] [PMID: 27484318]
Koob GF, Volkow ND. Neurocircuitry of addiction. Neuropsychopharmacology 2010; 35(1): 217-38.
[] [PMID: 19710631]
Wise RA. Dopamine and reward: the anhedonia hypothesis 30 years on. Neurotox Res 2008; 14(2-3): 169-83.
[] [PMID: 19073424]
Theodore S, Cass WA, Nath A, Maragos WF. Progress in understanding basal ganglia dysfunction as a common target for methamphetamine abuse and HIV-1 neurodegeneration. Curr HIV Res 2007; 5(3): 301-13.
[] [PMID: 17504172]
Kesby JP, Eyles DW, McGrath JJ, Scott JG. Dopamine, psychosis and schizophrenia: the widening gap between basic and clinical neuroscience. Transl Psychiatry 2018; 8(1): 30.
[] [PMID: 29382821]
Nath A, Anderson C, Jones M, et al. Neurotoxicity and dysfunction of dopaminergic systems associated with AIDS dementia. J Psychopharmacol (Oxford) 2000; 14(3): 222-7.
[] [PMID: 11106300]
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(5): 883-909.
[] [PMID: 18430470]
Li W, Li G, Steiner J, Nath A. Role of Tat protein in HIV neuropathogenesis. Neurotox Res 2009; 16(3): 205-20.
[] [PMID: 19526283]
Hudson L, Liu J, Nath A, et al. Detection of the human immunodeficiency virus regulatory protein tat in CNS tissues. J Neurovirol 2000; 6(2): 145-55.
[] [PMID: 10822328]
Parmentier HK, van Wichen DF, Meyling FH, Goudsmit J, Schuurman HJ. Epitopes of human immunodeficiency virus regulatory proteins tat, nef, and rev are expressed in normal human tissue. Am J Pathol 1992; 141(5): 1209-16.
[PMID: 1279980]
Silverstein PS, Shah A, Gupte R, et al. Methamphetamine toxicity and its implications during HIV-1 infection. J Neurovirol 2011; 17(5): 401-15.
[] [PMID: 21786077]
Kesby JP, Hubbard DT, Markou A, Semenova S. Expression of HIV gp120 protein increases sensitivity to the rewarding properties of methamphetamine in mice. Addict Biol 2014; 19(4): 593-605.
[] [PMID: 23252824]
Kesby JP, Heaton RK, Young JW, et al. Methamphetamine Exposure Combined with HIV-1 Disease or gp120 Expression: Comparison of Learning and Executive Functions in Humans and Mice. Neuropsychopharmacology 2015; 40(8): 1899-909.
[] [PMID: 25652249]
Maragos WF, Young KL, Turchan JT, et al. Human immunodeficiency virus-1 Tat protein and methamphetamine interact synergistically to impair striatal dopaminergic function. J Neurochem 2002; 83(4): 955-63.
[] [PMID: 12421368]
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(3): 925-35.
[] [PMID: 16338084]
Kim BO, Liu Y, Ruan Y, Xu ZC, Schantz L, He JJ. Neuropathologies in transgenic mice expressing human immunodeficiency virus type 1 Tat protein under the regulation of the astrocyte-specific glial fibrillary acidic protein promoter and doxycycline. Am J Pathol 2003; 162(5): 1693-707.
[] [PMID: 12707054]
Carey AN, Sypek EI, Singh HD, Kaufman MJ, McLaughlin JP. Expression of HIV-Tat protein is associated with learning and memory deficits in the mouse. Behav Brain Res 2012; 229(1): 48-56.
[] [PMID: 22197678]
Fitting S, Ignatowska-Jankowska BM, Bull C, et al. Synaptic dysfunction in the hippocampus accompanies learning and memory deficits in human immunodeficiency virus type-1 Tat transgenic mice. Biol Psychiatry 2013; 73(5): 443-53.
[] [PMID: 23218253]
Kesby JP, Markou A, Semenova S. Effects of HIV/TAT protein expression and chronic selegiline treatment on spatial memory, reversal learning and neurotransmitter levels in mice. Behav Brain Res 2016; 311: 131-40.
[] [PMID: 27211061]
Kesby JP, Fields JA, Chang A, Coban H, Achim CL, Semenova S. Effects of HIV-1 TAT protein and methamphetamine exposure on visual discrimination and executive function in mice. Behav Brain Res 2018; 349: 73-9.
[] [PMID: 29709610]
Kesby JP, Markou A, Semenova S. The effects of HIV-1 regulatory TAT protein expression on brain reward function, response to psychostimulants and delay-dependent memory in mice. Neuropharmacology 2016; 109: 205-15.
[] [PMID: 27316905]
Kesby JP, Najera JA, Romoli B, et al. HIV-1 TAT protein enhances sensitization to methamphetamine by affecting dopaminergic function. Brain Behav Immun 2017; 65(65): 210-21.
[] [PMID: 28495611]
Kesby JP, Chang A, Markou A, Semenova S. Modeling human methamphetamine use patterns in mice: chronic and binge methamphetamine exposure, reward function and neurochemistry. Addict Biol 2018; 23(1): 206-18.
[] [PMID: 28224681]
Ferré S, Fredholm BB, Morelli M, Popoli P, Fuxe K. Adenosine-dopamine receptor-receptor interactions as an integrative mechanism in the basal ganglia. Trends Neurosci 1997; 20(10): 482-7.
[] [PMID: 9347617]
Chesworth R, Brown RM, Kim JH, Ledent C, Lawrence AJ. Adenosine 2A receptors modulate reward behaviours for methamphetamine. Addict Biol 2016; 21(2): 407-21.
[] [PMID: 25612195]
Kavanagh KA, Schreiner DC, Levis SC, O’Neill CE, Bachtell RK. Role of adenosine receptor subtypes in methamphetamine reward and reinforcement. Neuropharmacology 2015; 89: 265-73.
[] [PMID: 25301277]
Shimazoe T, Yoshimatsu A, Kawashimo A, Watanabe S. Roles of adenosine A(1) and A(2A) receptors in the expression and development of methamphetamine-induced sensitization. Eur J Pharmacol 2000; 388(3): 249-54.
[] [PMID: 10675733]
Pierce RC, Kalivas PW. A circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants. Brain Res Brain Res Rev 1997; 25(2): 192-216.
[] [PMID: 9403138]
Brecht ML, O’Brien A, von Mayrhauser C, Anglin MD. Methamphetamine use behaviors and gender differences. Addict Behav 2004; 29(1): 89-106.
[] [PMID: 14667423]
Cheng WS, Garfein RS, Semple SJ, Strathdee SA, Zians JK, Patterson TL. Binge use and sex and drug use behaviors among HIV(-), heterosexual methamphetamine users in San Diego. Subst Use Misuse 2010; 45(1-2): 116-33.
[] [PMID: 20025442]
Cho AK, Melega WP. Patterns of methamphetamine abuse and their consequences. J Addict Dis 2002; 21(1): 21-34.
[] [PMID: 11831497]
Semple SJ, Patterson TL, Grant I. Binge use of methamphetamine among HIV-positive men who have sex with men: pilot data and HIV prevention implications. AIDS Educ Prev 2003; 15(2): 133-47.
[] [PMID: 12739790]
Simon SL, Richardson K, Dacey J, et al. A comparison of patterns of methamphetamine and cocaine use. J Addict Dis 2002; 21(1): 35-44.
[] [PMID: 11831498]
Sommers I, Baskin D, Baskin-Sommers A. Methamphetamine use among young adults: health and social consequences. Addict Behav 2006; 31(8): 1469-76.
[] [PMID: 16309848]
Burne TH, O’Loan J, McGrath JJ, Eyles DW. Hyperlocomotion associated with transient prenatal vitamin D deficiency is ameliorated by acute restraint. Behav Brain Res 2006; 174(1): 119-24.
[] [PMID: 16930734]
Watson CW, Sundermann EE, Hussain MA, et al. Effects of trauma, economic hardship, and stress on neurocognition and everyday function in HIV. Health Psychol 2019; 38(1): 33-42.
[] [PMID: 30372103]
Ballesteros-Yáñez I, Castillo CA, Merighi S, Gessi S. The Role of Adenosine Receptors in Psychostimulant Addiction. Front Pharmacol 2018; 8: 985.
[] [PMID: 29375384]
Kumar V, Sharma A. Adenosine: an endogenous modulator of innate immune system with therapeutic potential. Eur J Pharmacol 2009; 616(1-3): 7-15.
[] [PMID: 19464286]
Paris JJ, Singh HD, Ganno ML, Jackson P, McLaughlin JP. Anxiety-like behavior of mice produced by conditional central expression of the HIV-1 regulatory protein, Tat. Psychopharmacology (Berl) 2014; 231(11): 2349-60.
[] [PMID: 24352568]
Theodore S, Cass WA, Dwoskin LP, Maragos WF. HIV-1 protein Tat inhibits vesicular monoamine transporter-2 activity in rat striatum. Synapse 2012; 66(8): 755-7.
[] [PMID: 22517264]
Midde NM, Gomez AM, Zhu J. HIV-1 Tat protein decreases dopamine transporter cell surface expression and vesicular monoamine transporter-2 function in rat striatal synaptosomes. J Neuroimmune Pharmacol 2012; 7(3): 629-39.
[] [PMID: 22570010]

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Article Details

Year: 2019
Published on: 01 September, 2019
Page: [126 - 133]
Pages: 8
DOI: 10.2174/1570162X17666190703165408
Price: $65

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