Accumulating evidence suggests that opioid drug abuse per se directly exacerbates the neuropathology of HIV-1. Neuronal death is preceded by a prolonged period of synaptic culling and functional losses, and dendritic pathology that are presumably reversible. Opiate abuse potentiates the neuropathogenesis of HIV by synergistically increasing dendritic pathology (varicosity formation &pruning), while promoting spine losses (plasticity) in the striatum and hippocampal CA1 pyramidal neurons. Moreover, behavioral defects in both Morris water maze and rotarod performance coincide with synaptic losses and dendritic pathology in the absence of neuronal death, suggesting that neuronal injury and reduced synaptic connectivity underlie comorbid increases in HIV-associated neurological disorders (HAND). This represent a fundamental shift in our understanding of opioid drug action and propel the grant in novel directions. While death per se is significant, the interruption of events preceding neuron death may be more strategic therapeutically. We hypothesize that opioid-HIV interactive increases in neuron death are preceded by cumulative insults to synaptic organization and function that are non-lethal and assumed reversible.
Aim 1 will characterize the events underlying opioid and HIV-1-dependent neuronal dysfunction and/or injury in hippocampal neurons.
Aim 2 shall define the excitotoxic mechanisms by which opioids exacerbate HIV-1 Tat and gp120-induced neuronal dysfunction, injury, and/or death. Opioid and HIV-1-dependent alterations in synaptic function (altered membrane properties, EPSPs) spine morphology, and dendritic pathology (altered Na+, Ca2+, and ATP homeostasis) will be assessed. Lastly, aim 3 will identify the MOPr-expressing cellular sites of opioid action that exacerbate HIV-1-induced hippocampal neuronal injury, dysfunction and behavioral deficits in vivo. Cellular sites where opioids exacerbate Tat and gp120 actions in the hippocampus will be identified using floxed MOPr mice bred to astroglial specific GFAP, myeloid (microglial) specific lysozyme 2, and GABAergic forebrain neuron expressing Cre recombinase mice. Conditionally deleting MOPr at key sites will define the targets and associated mechanisms by which opioids exacerbate neuronal injury (including synaptic and dendritic pathology) and death, and neurocognitive defects (spatial learning-Morris water maze) in the hippocampus. Our long-term goal is to define the mechanisms by which opiate drug abuse exacerbates neurodegenerative and neurocognitive defects, and to identify the underlying signaling events that could be targeted therapeutically.
Emerging evidence suggests opioid drug abuse exacerbates the neurodegenerative effects of HIV-1 through cumulative insults that limit neuronal function long before the neuron is fatally injured. The grant proposes to examine the mechanisms underlying the functional decline of opioid-HIV-exposed hippocampal neurons involved in learning and memory. Events underlying early functional damage are likely to be reversible and may be excellent therapeutic targets.
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|Sorrell, Mary E; Hauser, Kurt F (2014) Ligand-gated purinergic receptors regulate HIV-1 Tat and morphine related neurotoxicity in primary mouse striatal neuron-glia co-cultures. J Neuroimmune Pharmacol 9:233-44|
|Dever, Seth M; Costin, Blair N; Xu, Ruqiang et al. (2014) Differential expression of the alternatively spliced OPRM1 isoform ?-opioid receptor-1K in HIV-infected individuals. AIDS 28:19-30|
|Ngwainmbi, Joy; De, Dipanjana D; Smith, Tricia H et al. (2014) Effects of HIV-1 Tat on enteric neuropathogenesis. J Neurosci 34:14243-51|
|Hauser, Kurt F; Knapp, Pamela E (2014) Interactions of HIV and drugs of abuse: the importance of glia, neural progenitors, and host genetic factors. Int Rev Neurobiol 118:231-313|
|El-Hage, Nazira; Dever, Seth M; Podhaizer, Elizabeth M et al. (2013) A novel bivalent HIV-1 entry inhibitor reveals fundamental differences in CCR5-*-opioid receptor interactions between human astroglia and microglia. AIDS 27:2181-90|
|Fitting, Sylvia; Ignatowska-Jankowska, Bogna M; Bull, Cecilia et al. (2013) Synaptic dysfunction in the hippocampus accompanies learning and memory deficits in human immunodeficiency virus type-1 Tat transgenic mice. Biol Psychiatry 73:443-53|
|Zou, Shiping; Fitting, Sylvia; Hahn, Yun-Kyung et al. (2011) Morphine potentiates neurodegenerative effects of HIV-1 Tat through actions at ýý-opioid receptor-expressing glia. Brain 134:3616-31|
|Zou, Shiping; El-Hage, Nazira; Podhaizer, Elizabeth M et al. (2011) PTEN gene silencing prevents HIV-1 gp120(IIIB)-induced degeneration of striatal neurons. J Neurovirol 17:41-9|
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