HIV-1 transgenic rats display an increase in [(3)H]dopamine uptake in the prefrontal cortex and striatum.
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 [(3)H]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 [(3)H]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.
Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, 715 Sumter Street, Columbia, SC, 29208, USA. zhuj@sccp.sc.edu.
Jun
J
Zhu
Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, Lexington, KY, 40536, USA.|Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, 40536, USA.
Yaxia
Y
Yuan
Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, 715 Sumter Street, Columbia, SC, 29208, USA.
Narasimha M
NM
Midde
Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, 715 Sumter Street, Columbia, SC, 29208, USA.
Adrian M
AM
Gomez
Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, 715 Sumter Street, Columbia, SC, 29208, USA.
Wei-Lun
WL
Sun
Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, 715 Sumter Street, Columbia, SC, 29208, USA.
Pamela M
PM
Quizon
Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, Lexington, KY, 40536, USA.|Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, 40536, USA.
Chang-Guo
CG
Zhan
D015526:AIDS Dementia Complex / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D000818:Animals; D003042:Cocaine / Q000031:analogs & derivatives / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism* / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D015497:HIV-1 / Q000472:pathogenicity / Q000502:physiology; D007700:Kinetics; D008297:Male; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D055647:Rats, Transgenic; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism; D014316:Tritium; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics* / Q000378:metabolism
D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D054322:tat Gene Products, Human Immunodeficiency Virus; D014316:Tritium; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D003042:Cocaine; D004298:Dopamine
Dopamine transporter; Dopamine uptake; HIV-1 Tat; Striatum; Trafficking; Transgenic rat