In vivo microdialysis in awake, freely moving rats demonstrates HIV-1 Tat-induced alterations in dopamine transmission

Abstract

Individuals infected with human immunodeficiency virus (HIV) may develop neuropsychological impairment, and a modest percentage may progress to HIV-associated dementia (HAD). Research using human and nonhuman, in vitro and in vivo models, demonstrates that subcortical dopamine (DA) systems may be particularly vulnerable to HIV-induced neurodegeneration. The goal of the current investigation is to provide an understanding of the extent to which the HIV-1 protein Tat induces alterations in striatal DA transmission using in vivo brain microdialysis in awake, freely moving rats. The current study was designed to investigate Tat-induced neuronal dysfunction between 24-h and 48-h post-Tat administration, and demonstrates a reduction in evoked DA for the Tat-treated group relative to vehicle-treated group at 24 and 48 h. The Tat-induced reduction of DA overflow by 24 h suggests dysfunction of nerve terminals, and a compromised DA system in Tat-treated animals. Furthermore, the current study provides direct support for HIV-associated decline of DA function at a systemic level, helping to characterize the functional outcome of the relatively large amount of research on the molecular and behavioral levels of HIV-induced neurotoxicity. This initial study may provide additional characteristics of Tat-induced neuronal dysfunction to inform research on therapeutic intervention, and it provides a springboard for future in vivo research currently needed in the field.

Fig. 1

Schematic representation of probe placements. Anterior/posterior coordinates located between +1.0 mm and +1.3 mm relative to Bregma.

Fig. 2

Validation of successful infusion of Tat_1–86 into the rat NAcc. (A) Immunofluorescent image (100×; probe-tip) of Tat antibody (fluorescent green) present in Tat-treated animal striatal section. (B) Immunofluorescent image (100×; probe-tip) of Tat antibody in vehicle-treated animal (control animal). Note: Immunofluorescent image of negative control (not shown) no different than vehicle-treated control animal.

Fig. 3

Effect of intrastriatal infusion of Tat or vehicle control on raw striatal DA levels (A) and percent of baseline (B) within Session 1. A significant Tat-induced reduction in K⁺-evoked DA levels was present 24 h after Tat infusion. Note: *P < 0.05 for main effect (area under curve and planned comparison of collections 6 and 7); #P < 0.001 for time × treatment interaction.

Fig. 4

Effect of intrastriatal infusion of Tat or vehicle control on raw striatal DA levels (A) and percent of baseline (B) within Session 2. A significant Tat-induced reduction in K⁺-evoked DA levels was present 48 h after Tat infusion. Note: *P < 0.05 for main effect (area under curve and planned comparison of collections 6 and 7); #P < 0.001 for time × treatment interaction.