HIV transactivator of transcription enhances methamphetamine-induced Parkinson’s-like behavior in the rats

Abstract

Abuse of methamphetamine (MA) increases the risk of infection of HIV-1, induces considerable neurotoxicity in several brain regions, and impairs the motor and cognitive function in individuals. HIV-1 transactivator of transcription (Tat) has also shown the potent capability to induce neuronal death and impaired brain function. The present study aims to study the synergistic effect of MA and Tat on cytokine synthesis in substantia nigra, striatal dopamine content, and behavioral performance in the rats. Although increased expression of cytokines (interleukin-1β and tumor necrosis factor-α) was observed in the substantia nigra in the rats receiving either MA or Tat alone, a combination of MA and Tat induced a larger and more sustained upregulation of cytokines. In the rats receiving either MA or Tat alone, significant loss in striatal dopamine content was found, which was further exacerbated in the rats receiving both MA and Tat. In the rats receiving either MA or Tat alone, significantly lower performance in the rotarod test and open-field test was observed, whereas the rats receiving both MA and Tat showed more sustained behavioral impairments. These results suggested that Tat protein synergized with MA to induce central neuroinflammation and impair the dopaminergic transmission, thus leading to sustained Parkinson’s-like behavior.

HIV, Tat and dopamine transmission

“…Some patients with HIV dementia develop acute onset Parkinsonism and dystonia when treated with dopamine receptor antagonists (Hriso et al, 1991), and patients on cART can also develop parkinsonism (Tisch and Brew, 2009). In methamphetamine-treated rodents, an intra-nigral infusion of 10 μg/μL (approximately 1 mM) Tat was shown to exacerbate Parkinson-like locomotor deficit (Liu et al, 2014). This is consistent with reports showing methamphetamine-induced behavioral sensitization were enhanced in HIV-1 Tg rats (Kass et al, 2010).…”

“…Similarly, in SH-SY5Y (neuroblastoma) cells, Tat and methamphetamine together induce a small but significant increase in apoptosis (Qi et al, 2011). In methamphetamine treated rats, where Tat was delivered directly to the substantia nigra, Tat potentiated methamphetamine induced dopamine deficits in the striatum and enhanced deficits in dopamine-driven behaviors such as the rotarod and open field tests (Liu et al, 2014). Rodents treated with both Tat and methamphetamine show 60% – 78% reductions in the basal ganglia dopamine levels, particularly striatal dopamine levels.…”

HIV Tat and Morphine-induced Neurodegeneration in a Beclin 1 Hemizygous Mouse Model

“…We saw no observable effect of Tat on rotarod performance for either strain of mice, but a significant effect of morphine (Figure 4.6). Studies which have looked at the effect of HIV or its viral proteins on rotarod performance have been quite varied in their results with some studies finding significant impairment in accelerated rotarod performance [409,[414][415][416][417], and some studies finding no differences [214,396,399,[418][419][420], as we have here. There were, however, two significant differences between those studies and the ones performed here.…”

“…As such, glutamate uptake and dopamine release from these neurons are key aspects of function. One study on the effect of Tat and methamphetamine in rat striatal neurons showed that the treatment lead to striatal dopamine deficit which contributed to the manifestation of motor impairment [416]. The evaluation of neuronal viability performed here also requires further exploration into the mechanisms of neuronal death whether apoptosis dependent or independent pathways.…”

“…Now that we have found that reduced Beclin 1 in glia can reduce the Tat and morphine toxicity to neurons, future studies will examine neuronal functionality which can be just as important as neuronal viability. These would include studies on neurotransmitter release which is reported to be dysregulated with Tat exposure [416]. For example, the striatum is a location with predominantly GABAergic medium spiny neurons but receives both dopaminergic and glutamatergic inputs from various sources [412].…”