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HIV-1 transgenic rats display an increase in [3H]dopamine uptake in the prefrontal cortex and striatum

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Abstract

HIV viral proteins within the central nervous system are associated with the development of neurocognitive impairments in HIV-infected individuals. Dopamine transporter (DAT)-mediated dopamine transport is critical for normal dopamine homeostasis. Abnormal dopaminergic transmission has been implicated as a risk determinant of HIV-induced neurocognitive impairments. Our published work has demonstrated that transactivator of transcription (Tat)-induced inhibition of DAT is mediated by allosteric binding site(s) on DAT, not the interaction with the dopamine uptake site. The present study investigated whether impaired DAT function induced by Tat exposure in vitro can be documented in HIV-1 transgenic (HIV-1Tg) rats. We assessed kinetic analyses of [3H]dopamine uptake into prefrontal and striatal synaptosomes of HIV-1Tg and Fisher 344 rats. Compared with Fisher 344 rats, the capacity of dopamine transport in the prefrontal cortex (PFC) and striatum of HIV-1Tg rats was increased by 34 and 32 %, respectively. Assessment of surface biotinylation indicated that DAT expression in the plasma membrane was reduced in PFC and enhanced in striatum, respectively, of HIV-1Tg rats. While the maximal binding sites (B max) of [3H]WIN 35,428 was decreased in striatum of HIV-1Tg rats, an increase in DAT turnover proportion was found, relative to Fisher 344 rats. Together, these findings suggest that neuroadaptive changes in DAT function are evidenced in the HIV-1Tg rats, perhaps compensating for viral-protein-induced abnormal dopaminergic transmission. Thus, our study provides novel insights into understanding mechanism underlying neurocognitive impairment evident in neuroAIDS.

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Abbreviations

AIDS:

Acquired immunodeficiency syndrome

B max :

Maximal number of [3H]ligand binding sites

DA:

Dopamine

DAT:

Dopamine transporter

EDTA:

Ethylenediamine tetraacetic acid

EDC:

1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide

GBR 12909:

1-[2-(bis[4-fluorophenyl]methoxy)ethyl]-4-[3-phenylpropyl]piperazine

HBS-TE:

HEPES-buffered saline with Tween 20 and EDTA

hDAT:

Human dopamine transporter

HIV:

Human immunodeficiency virus

HAD:

HIV-associated dementia

K d :

Equilibrium dissociation constant

K m :

Michaelis-Menten constant

Tat:

Transactivator of transcription

Tween 20:

Polyethylene glycol sorbitan monolaurate

V max :

Maximal velocity

WIN 35,428:

2β-Carbomethoxy-3-β-(4-fluorophenyl)tropane

MD:

Molecular dynamics

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Acknowledgments

This research was supported by grants from the National Institute on Drug Abuse to Jun Zhu (R01DA035714, R03DA024275, and R03DA026721). This work was previously presented at the 12th International Symposium on NeuroVirology; October 29–November 2, 2013, Washington D.C., USA. We would like to acknowledge Richard Sterling McCain Jr for his excellent technical assistance.

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Authors and Affiliations

  1. Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, 715 Sumter Street, Columbia, SC, 29208, USA

    Jun Zhu, Narasimha M. Midde, Adrian M. Gomez, Wei-Lun Sun & Pamela M. Quizon

  2. Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, Lexington, KY, 40536, USA

    Yaxia Yuan & Chang-Guo Zhan

  3. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, 40536, USA

    Yaxia Yuan & Chang-Guo Zhan

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  1. Jun Zhu
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  2. Yaxia Yuan
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  3. Narasimha M. Midde
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Correspondence to Jun Zhu.

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Zhu, J., Yuan, Y., Midde, N.M. et al. HIV-1 transgenic rats display an increase in [3H]dopamine uptake in the prefrontal cortex and striatum. J. Neurovirol. 22, 282–292 (2016). https://doi.org/10.1007/s13365-015-0391-6

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