HIV-1 infected individuals who are injecting opioid drugs show increased cognitive defects and undergo an accelerated rate of progression to AIDS. Accumulating evidence suggests that opioid drug abuse intrinsically exacerbates the pathogenesis of HIV-1. We have found that neuronal death is preceded by a prolonged period of synaptic culling, functional losses, and dendritic pathology that are presumed reversible. Importantly, opioid abuse potentiates the neuropathogenesis of HIV-1 by synergistically increasing dendritic pathology (varicosity formation, beading, fragmentation, pruning), while promoting additive dendritic spine losses (plasticity). This has been verified in medium spiny neurons (MSN) of the striatum and synaptic pruning has been confirmed electron microscopically. Moreover, behavioral defects in locomotor activity are accompanied by synaptic losses and dendritic pathology in the absence of demonstrable neuron death, suggesting that sublethal neuronal injury and reduced synaptic connectivity underlie the ability of opioids to aggravate HIV-1-associated neurological disorders (HAND). While death per se is significant, the interruption of events preceding neuron death may be more strategic therapeutically. This grant will focus on the functional level of MSN by investigating the underlying physiological mechanisms of opioid HIV-induced excitotoxicity. It is hypothesized that Tat induces changes in the cellular homeostasis and excitability of MSN, that are exacerbated by opioid drugs through a complex sequence of events involving OR-mediated pathways. In vitro approaches are being proposed by assessing the effects of opioid drug and HIV-1 Tat-induced neurotoxicity in dissociated cortical- striatal cell cultures. Whole-cell patch-clamp recordings will be conducted in voltage- and current-clamp mode by assessing action potentials as well as sodium, potassium, AMPA, NMDA, and calcium (Ca2+) currents. The role of OR will be elucidated by applying pharmacological (OR antagonists), genetic (OR knockout mice) and silencing (silencing NMDAR) strategies to identify mechanisms underlying opioid + HIV protein interaction. To sort out whether opioids exacerbate the excitotoxic effects of Tat in the striatum via OR on MSN we will conduct experiments in vivo using two types of Cre-lox mice. Conditionally deleting OR at key sites will define the targets and associated mechanisms by which opioids exacerbate neuronal excitability (action potentials, ion channel activity, ion imaging, mitochondrial membrane potential), injury (including dendritic pathology and spine density), and behavioral defects (locomotor activity) in the striatum.

Public Health Relevance

Opioids can exacerbate the excitotoxic effects of HIV-1 products by activating opioid receptor (OR)-mediated pathways in striatal neurons. Excitotoxicity involves overactivation of NMDA and AMPA receptors, a loss in cellular homeostasis, and calcium overload, which can result in a loss of synaptic spines,sublethal dendritic injury, and behavioral deficits. Finding treatments for preventing or reversing sublethal neuronal injury that precedes permanent neuronal losses will determine best therapeutic strategies for limiting neurocognitive deficits seen in HIV-1 positive drug abusers.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Transition Award (R00)
Project #
5R00DA033878-05
Application #
9275948
Study Section
Special Emphasis Panel (NSS)
Program Officer
Sorensen, Roger
Project Start
2015-01-01
Project End
2018-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
5
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Hermes, Douglas J; Xu, Changqing; Poklis, Justin L et al. (2018) Neuroprotective effects of fatty acid amide hydrolase catabolic enzyme inhibition in a HIV-1 Tat model of neuroAIDS. Neuropharmacology 141:55-65
Fitting, Sylvia; McLaurin, Kristen A; Booze, Rosemarie M et al. (2018) Dose-dependent neurocognitive deficits following postnatal day 10 HIV-1 viral protein exposure: Relationship to hippocampal anatomy parameters. Int J Dev Neurosci 65:66-82
Xu, Changqing; Hermes, Douglas J; Nwanguma, Blessing et al. (2017) Endocannabinoids exert CB1 receptor-mediated neuroprotective effects in models of neuronal damage induced by HIV-1 Tat protein. Mol Cell Neurosci 83:92-102
Marks, William D; Paris, Jason J; Schier, Christina J et al. (2016) HIV-1 Tat causes cognitive deficits and selective loss of parvalbumin, somatostatin, and neuronal nitric oxide synthase expressing hippocampal CA1 interneuron subpopulations. J Neurovirol 22:747-762
Fitting, Sylvia; Stevens, David L; Khan, Fayez A et al. (2016) Morphine Tolerance and Physical Dependence Are Altered in Conditional HIV-1 Tat Transgenic Mice. J Pharmacol Exp Ther 356:96-105
Guedia, Joy; Brun, Paola; Bhave, Sukhada et al. (2016) HIV-1 Tat exacerbates lipopolysaccharide-induced cytokine release via TLR4 signaling in the enteric nervous system. Sci Rep 6:31203
Xu, Changqing; Fitting, Sylvia (2016) Inhibition of GABAergic Neurotransmission by HIV-1 Tat and Opioid Treatment in the Striatum Involves ?-Opioid Receptors. Front Neurosci 10:497
Xu, Changqing; Hermes, Douglas J; Mackie, Ken et al. (2016) Cannabinoids Occlude the HIV-1 Tat-Induced Decrease in GABAergic Neurotransmission in Prefrontal Cortex Slices. J Neuroimmune Pharmacol 11:316-31
Fitting, Sylvia; Booze, Rosemarie M; Mactutus, Charles F (2015) HIV-1 proteins, Tat and gp120, target the developing dopamine system. Curr HIV Res 13:21-42
Fitting, S; Ngwainmbi, J; Kang, M et al. (2015) Sensitization of enteric neurons to morphine by HIV-1 Tat protein. Neurogastroenterol Motil 27:468-80

Showing the most recent 10 out of 12 publications