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

Abstract

There are roughly 30 to 40 million HIV infected individuals in the world as of December 2007, and drug abuse directly contributes to one-third of all HIV-infections in the United States. Antiretroviral therapy has increased the lifespan of HIV-seropositives, but CNS function often remains diminished, effectively decreasing quality of life. A modest proportion may develop HIV-associated dementia, the severity and progression of which is increased with drug abuse. HIV and drugs of abuse in the CNS target subcortical brain structures and DA systems in particular. This toxicity is mediated by a number of neurotoxic mechanisms, including but not limited to, aberrant immune response and oxidative stress. Therefore, novel therapeutic strategies must be developed that can address a wide variety of disparate neurotoxic mechanisms and apoptotic cascades. This paper reviews the research pertaining to the where, what, and how of HIV and cocaine/methamphetamine toxicity in the CNS. Specifically, where these toxins most affect the brain, what aspects of the virus are neurotoxic, and how these toxins mediate neurotoxicity.

Human Immunodeficiency Virus (HIV) Infection of Human Macrophages Is Increased by Dopamine

“…These drugs act in concert with HIV to accelerate neuropathogenesis by disrupting the blood-brain barrier, promoting neuroinflammation and altering proliferation and cytokine production in CNS cells. 17,18,[53][54][55] The mechanism(s) by which drugs of abuse mediate these effects are not well understood, but one major commonality among psychostimulants is that their use increases the concentration of extracellular of DA within the CNS. 27,28,56 Dopamine is a major catecholamine neurotransmitter in the CNS and is involved in diverse functions including control of locomotion, cognition, neuroendocrine secretion, and positive reinforcement.…”

“…The enhanced neuropathology would be particularly pronounced in DA-rich regions of the brain, such as the basal ganglia, providing an explanation for the higher levels of neurological damage seen in these regions during HIV infection. 18,59 The high levels of extracellular DA produced by drug abuse could also potentiate the development of HIV-induced neurological damage by modulating intracellular signaling and contributing to the functional dysregulation of both infected and uninfected macrophages.…”

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

“…In rat fetal midbrain primary culture cells, incubation with Tat protein causes reductions in [ 3 H]WIN 35,428 binding, which was associated with Tat-induced neurotoxicity (Aksenova et al, 2006). Taken together, these results suggest that Tat protein-induced neurotoxicity, at least in part, is mediated through reduced DAT activity and that a combination of Tat protein and abused drugs enhances neurotoxicity in a synergistic manner (Ferris et al, 2008).…”

Inflammation Effects on Motivation and Motor Activity: Role of Dopamine

“…For example, DAT-expressing cells transfected with constitutively activate MAPK kinase (MEK) show increased DA reuptake (Vmax), whereas the treatment of rat striatal synaptosomes with MEK inhibitors decreased DA reuptake in a concentration-and time-dependent manner (Moron et al, 2003). Furthermore, subjects with neuropsychiatric disturbances as a result of HIV infection and subsequent neuroinflammation are thought to have increased expression of DAT (Ferris et al, 2008;Gelman et al, 2006). Therefore, reduced synaptic DA following chronic exposure to inflammatory cytokines may be mediated, in part, by increased DAT expression or function (Figure 2).…”