HIV-1 Tat Protein-Induced Rapid and Reversible Decrease in [³H]Dopamine Uptake: Dissociation of [³H]Dopamine Uptake and [³H]2β-Carbomethoxy-3-β-(4-fluorophenyl)tropane (WIN 35,428) Binding in Rat Striatal Synaptosomes

Abstract

Human immunodeficiency virus (HIV)-1 Tat protein plays a key role in the pathogenesis of both HIV-1-associated cognitivemotor disorder and drug abuse. Dopamine (DA) transporter (DAT) function is strikingly altered in patients with HIV-1-associated dementia and a history of chronic drug abuse. This study is the first in vitro evaluation of potential mechanisms underlying the effects of Tat protein on DAT function. Rat striatal synaptosomes were incubated with recombinant Tat

Effects of Conditional Central Expression of HIV-1 Tat Protein to Potentiate Cocaine-Mediated Psychostimulation and Reward Among Male Mice

“…Consistent with these results, exogenous microinjection of a 72-amino-acid Tat protein directly into the nucleus accumbens (NAc) of rats increased acute locomotor responding to cocaine (Harrod et al, 2008). These results are logical, given reports that Tat protein allosterically modulates DAT in a dose-dependent and reversible manner (Aksenov et al, 2001;Ferris et al, 2009;Zhu et al, 2009Zhu et al, , 2011 H]DA uptake into striatal synaptosomes time-and concentration-dependently (Zhu et al, 2009). These actions may directly contribute to decreased DA recycling, subsequently increasing extracellular DA in the NAc to potentiate the psychostimulant effects of cocaine when both are present (Ferris et al, 2009(Ferris et al, , 2010.…”

“…In fact, specific mutations within the first exon of the Tat gene correlate with HIV clade-specific differences in the prevalence of HIV dementia (Sacktor et al, 2009) and human neuron toxicity (Rao et al, 2008;Mishra et al, 2008). Furthermore, Tat exposure is known to contribute to dysfunction of the dopaminergic system Yao and Buch, 2012), influencing DA recycling (Ferris et al, 2009), uptake kinetics (Zhu et al, 2009), and causing rapid DA transporter (DAT) dysfunction (Wallace et al, 2006;Zhu et al, 2011). Given that drug reward is thought to involve the mesolimbic DA pathway, the ability of Tat to promote dopaminergic dysfunction implies a biological mechanism by which Tat may modulate drug reinforcement, but behavioral determinations are lacking.…”

Time and time again: Temporal processing demands implicate perceptual and gating deficits in the HIV-1 transgenic rat

“…HIV-1 Tg rats also display alterations in the DA system, with significantly lower MAO-A levels than control animals, as well as lower levels of tyrosine hydroxylase after treatment with methamphetamine (Moran et al 2012). In vitro studies have shown that DAT is targeted by HIV-1 proteins Tat and gp120, resulting in transporter impairment (Aksenov et al 2008;Ferris et al 2009;Midde et al 2013;Zhu et al 2009;Zhu et al 2011), due to direct protein-protein interactions (Zhu et al 2009) involving an allosteric modulation of DAT by the Tat protein (Zhu et al 2011). In addition, DA-dependent signaling has been identified as a mechanism of HIV-1 protein neurotoxicity (Aksenova et al 2006;Silvers et al 2007;Wallace et al 2006).…”

HIV‐1 protein Tat inhibits vesicular monoamine transporter‐2 activity in rat striatum

“…The HIV-1 transactivator of transcription protein (Tat) has been shown to play an active role in HIV-1-induced neurodegeneration (Theodore et al, 2007). In addition to the widely known neurotoxic actions of Tat, recent evidence has uncovered a role for Tat in altering normal function of the dopamine (DA) transporter, which is essential for reuptake of DA released into the cytoplasm (Zhu et al, 2009). It is not known whether Tat has any effects on the function of vesicular monoamine transporter-2 (VMAT-2) that is involved in sequestering DA within the synaptic vesicles.…”

“…Because methamphetamine has been shown to elevate cytoplasmic levels of DA, presumably by inhibition of VMAT-2 function (Brown et al, 2000), the net result in HIV-1 infected-methamphetamine abusing patients could be the generation of pathologically elevated levels of cytosolic DA that could lead to increased free radical levels within the terminals that in turn may lead to more severe neurodegeneration in this patient population compared with HIV-1 infected individuals that do not abuse methamphetamine. It is important to point out that Tat has also been demonstrated to inhibit DA transporter function (Zhu et al, 2009), which may have contributed to the reduction in K+-evoked DA release. Thus, there is likely to be a complex interplay between these two processes that require further investigation.…”