D1/NMDA Receptors and Concurrent Methamphetamine+HIV-1 Tat Neurotoxicity

Abstract

The interactive effects of HIV-1 infection and methamphetamine (METH) abuse in producing cognitive dysfunction represent a serious medical problem; however, the neural mechanisms underlying this interactive neurotoxicity remain elusive. In this study, we report that a combination of low, sub-toxic doses of METH + HIV-1 Tat 1–86 B, but not METH + HIV-1 gp120, directly induces death of rodent midbrain neurons in vitro. The effects of D1- and NMDA-receptor specific antagonists (SCH23390 and MK-801, respectively) on the neurotoxicity of different doses of METH or HIV-1 Tat alone and on the METH + HIV-1Tat interaction in midbrain neuronal cultures suggest that the induction of the cell death cascade by METH and Tat requires both dopaminergic (D1) and N-methyl D-aspartate (NMDA) receptor-mediated signaling. This interactive METH+Tat neurotoxicity does not occur in cultures of hippocampal neurons, which are predominately glutamatergic, express very low levels of dopamine receptors, and have no functional dopamine transporter (DAT). Thus, the presence of a subpopulation of neurons capable of dopamine release/uptake is essential for METH+Tat induction of the cell death cascade. Overall, our results support the hypothesis that METH and HIV-1 Tat disrupt the normal conjunction of signaling between D1 and NMDA receptors, resulting in neural dysfunction and death.

Methamphetamine potentiates HIV-1gp120-induced microglial neurotoxic activity by enhancing microglial outward K + current

“…It has been shown that Meth accelerates HIV infection and synergistically potentiates gp120- and Tat-associated neurotoxicity (Maragos et al, 2002; Nair et al, 2009; Nair and Samikkannu, 2012; Silverstein et al, 2012; Turchan et al, 2001). Multiple mechanisms for Meth-induced potentiation have been proposed including upregulation of HIV-1 co-receptors CXCR4 and CCR5 expression (Nair and Saiyed, 2011; Nair et al, 2009), interaction with NMDA receptors producing excitotoxic neural injury (Aksenov et al, 2012), oxidative stress (Purohit et al, 2011; Shah et al, 2013), and disruption of dopaminergic function (Aksenov et al, 2012; Purohit et al, 2011) and the blood-brain barrier (Mahajan et al, 2008). In this study, we found that Meth and gp120 enhance microglial expression of K v 1.3 channel protein and outward K current leading to an increased microglial production of TNFα, IL-1β, and NO and resultant enhancement of microglial neurotoxic activity.…”

HIV-1 Tat-Mediated Calcium Dysregulation and Neuronal Dysfunction in Vulnerable Brain Regions

“…Interestingly, a recent study reveals that D1R expression is significantly increased in the brain of HIV-1 Tg rats [73]. Further, death of midbrain dopaminergic neurons induced by Tat, as well as by combined sub-toxic doses of Tat and methamphetamine, is attenuated by inhibition of D1Rs [74, 75]. Because D1R activation facilitates the cAMP/PKA cascade, it is possible that increased D1R expression in HIV-infected brains may lead to enhanced phosphorylation of NMDAR, thereby inducing additional increase of Ca 2+ influx in neurons.…”

Interactive HIV-1 Tat and Morphine-Induced Synaptodendritic Injury Is Triggered through Focal Disruptions in Na+ Influx, Mitochondrial Instability, and Ca2+ Overload

“…Tat has been shown to activate glutamatergic NMDA receptors (NMDARs) through a variety of direct and indirect mechanisms (Magnuson et al, 1995;Haughey et al, 2001;Pérez et al, 2001;Li et al, 2008;Aksenov et al, 2012). Tat mediates neurotoxic glutamate release, which activates AMPA receptors (AMPARs) that can upregulate NMDA-mediated toxicity (Longordo et al, 2006), leading to dendritic structural and functional defects observed in HIV-1 infected individuals (Mattson et al, 2005).…”