Neurotoxicity of HIV-1 Tat protein: Involvement of D1 dopamine receptor☆

Abstract

Neurotoxic viral proteins released from HIV-infected cells are believed to play a major role in the pathogenesis of the dementia displayed in a significant number of AIDS patients. HIV-1 associated neuropathology severely affects dopaminergic regions of the brain. Growing evidence indicates that HIV-1 neurotoxic proteins, such as Tat may affect the function of the dopamine transmission system. In turn, molecular components of dopamine neurotransmission may participate in a complex network of Tat-induced cell responses which result in neurodegeneration. In this study we investigated whether D1 dopamine receptors are involved in the mechanism of Tat neurotoxicity in primary rat neuronal cell cultures. We found that in rat midbrain cell cultures, which express significant levels of D1 dopamine receptors, the specific D1 antagonist SCH 23390 attenuates the cell death caused by HIV-1 Tat. In rat hippocampal cell cultures, where the expression of D1 receptors is low, SCH 23390 did not change the toxicity of Tat. Thus, the protective effect of SCH 23390 in rat primary neuronal cell cultures correlates with the level of D1 receptor protein expression. Our results provide further evidence for the involvement of the dopaminergic transmission system in the mechanism of HIV-1 Tat neurotoxicity.

Drugs of Abuse, Dopamine, and HIV-Associated Neurocognitive Disorders/HIV-Associated Dementia

“…Thus, it is plausible that cumulative oxidative stress generated by HIV proteins and dopamine metabolism may potentiate severity and accelerate progression of HAND/HAD. It is interesting to note that dopamine receptor-1 is involved in Tat-induced neurotoxicity [77] where oxidative stress may play a contributory role.…”

Neurotoxic profiles of HIV, psychostimulant drugs of abuse, and their concerted effect on the brain: Current status of dopamine system vulnerability in NeuroAIDS

“…Complete review of glutamatergic NMDAR exceeds the purpose of the review (see King et al, 2006). Nevertheless, Tat/NMDAR mediated toxicity likely effects DA systems; and research in our laboratory (Silvers et al, 2007) has recently demonstrated a D1 receptor/Tat interaction, whereby Tat-induced neurotoxicity to rat fetal midbrain cell cultures was abrogated by a D1 receptor antagonist (SCH23390) where D1 receptor binding was abundant. Interestingly, this study demonstrated a lack of SCH23390-mediated attenuation of Tat-induced neurotoxicity to fetal hippocampal culture, where D1 receptor binding is low.…”

“…Interestingly, this study demonstrated a lack of SCH23390-mediated attenuation of Tat-induced neurotoxicity to fetal hippocampal culture, where D1 receptor binding is low. The correlation between D1 receptor binding and SCH23390 protection from Tat-toxicity demonstrates a possible role for D1 receptors in the neurotoxic mechanism of Tat (Silvers et al, 2007). Furthermore, based on evidence for NMDAR/D1 regulatory and structural heteromeric interactions (Cepeda and Levine, 2006;Missale et al, 2006), Silvers et al (in press) speculate a possible NMDAR/D1 reciprocal regulation of pro-apoptotic cascades, mediated by Tat and/or Tat-induced ROS.…”

“…Taken together, these studies (Aksenov et al, 2001(Aksenov et al, , 2003 provide evidence that HIV proteins may directly increase oxidative stress to neurons by inducing mitochondrial dysfunction and through interactions with membrane or cytosolic bound proteins; thus, they may play an initial, "upstream" role in neuronal injury/death, while immune response may occur later "downstream." It may also be the case that HIV-induced ROS interacts with these proteins to trigger pro-apoptotic signaling cascades, or additional oxidative stress in neurons Kruman et al, 1998;Silvers et al, 2007). Table 2 provides representative research performed on DA systems within the last few years which demonstrate a possible time-course of effects following an acute injection or administration of Tat and/or gp120.…”

Different effects of selective dopamine uptake inhibitors, GBR 12909 and WIN 35428, on HIV-1 Tat toxicity in rat fetal midbrain neurons

“…Recently, Tat was shown to increase the potassium-evoked outflow of DA early (2 hours) after the injection into rat nucleus accumbens (Ferris et al, 2007). The protective action of the D1 receptor selective antagonist, SCH 23390, against Tat and Tat+cocaine in vitro , Silvers et al, 2007 suggested that concurrent changes in DA homeostasis induced by Tat and cocaine may contribute to their combined toxicity.…”