In this competing renewal application, we will explore the hypothesis that estrogenic compounds may serve as protective agents for the synergistic effects of cocaine/HIV proteins on producing synaptic impairments in the nucleus accumbens, a critical brain region involved in the motor and cognitive dysfunction associated with HIV-1 associated neurocognitive disorder (HAND) and recognized as the main target of the mesotelencephalic dopamine system and the main striatal waystation for circuits of prefrontal origin.
The specific aims are: 1) To investigate the role of cocaine/HIV-1 protein-induced synaptic impairment and estrogenic modulation of neuroplasticity. The proposed in vitro experiments will further determine the mechanisms of estrogenic activity and test novel soy isoflavone compounds as potential estrogen ?-receptor modulators of HIV-protein induced synaptic impairment. 2) To determine the role of estrogen(s) in modulating nucleus accumbens dopaminergic synaptic plasticity following repeated cocaine in chronic HIV-1 protein exposure models. The effects of HIV-1 protein+cocaine on dopaminergic neurochemistry will be assessed using in vivo microdialysis in ovariectomized female HIV-1 transgenic animals. The ability of estrogen/soy isoflavones+ cocaine to produce DAT dysfunction/protection under physiological conditions will be assessed and the behavioral/pathological consequences will be determined. 3) To determine the role of synaptic plasticity in HIV-1 protein+cocaine cognitive behavioral impairments and estrogenic therapeutic effects. Estrogen(s) will be used to modulate cognition and dopamine markers following cocaine and HIV-1, providing insight into potential neuroprotective mechanisms and therapeutic strategies. Investigations will focus on quantifying spine density changes with respect to regulators of nucleus accumbens medium spiny neurons and prefrontal cortical neuronal plasticity. The ultimate goal of this research is to identify sensitive targets and unique pharmacological interventions (estrogen ?-receptor modulators) for preventing cognitive and motor dysfunction (HAND) following cocaine abuse in HIV-1+ special populations.

Public Health Relevance

With over 33 million HIV-1 infections globally, and with the consequent the transition of AIDS from an acute to a chronic disorder owing to the tremendous success of combination antiretroviral therapy regimens, if up to 50% of the current infections develop neurocognitive deficits, a looming health crisis is apparent for millions. This is particularly true where the treatment disparities may lead to interactions with co-morbid drugs of abuse (such as cocaine), resulting in premature onset of brain dysfunction. In this project, we will explore estrogenic compounds as protective agents for the synergistic effects of cocaine/HIV proteins on producing synaptic impairments in the nucleus accumbens, a critical brain region involved in the motor and cognitive dysfunction associated with HIV-1 associated neurocognitive disorder (HAND) and recognized as the main target of the mesotelencephalic dopamine system and the main striatal way station for circuits of prefrontal origin.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
7R01DA013137-13
Application #
8370502
Study Section
Special Emphasis Panel (ZRG1-AARR-C (02))
Program Officer
Frankenheim, Jerry
Project Start
1999-09-01
Project End
2015-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
13
Fiscal Year
2013
Total Cost
$348,000
Indirect Cost
$108,000
Name
University of South Carolina at Columbia
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
041387846
City
Columbia
State
SC
Country
United States
Zip Code
29208
Li, Hailong; Aksenova, Marina; Bertrand, Sarah J et al. (2016) Quantification of Filamentous Actin (F-actin) Puncta in Rat Cortical Neurons. J Vis Exp :e53697
McLaurin, Kristen A; Booze, Rosemarie M; Mactutus, Charles F (2016) Progression of temporal processing deficits in the HIV-1 transgenic rat. Sci Rep 6:32831
Moran, Landhing M; Hord, Lauren L; Booze, Rosemarie M et al. (2016) The role of sensory modality in prepulse inhibition: An ontogenetic study. Dev Psychobiol 58:211-22
McLaurin, Kristen A; Moran, Landhing M; Li, Hailong et al. (2016) A Gap in Time: Extending our Knowledge of Temporal Processing Deficits in the HIV-1 Transgenic Rat. J Neuroimmune Pharmacol :
Kaminski, R; Bella, R; Yin, C et al. (2016) Excision of HIV-1 DNA by gene editing: a proof-of-concept in vivo study. Gene Ther 23:690-5
McLaurin, Kristen A; Booze, Rosemarie M; Mactutus, Charles F (2016) Selective developmental alterations in The HIV-1 transgenic rat: Opportunities for diagnosis of pediatric HIV-1. J Neurovirol :
McLaurin, Kristen A; Mactutus, Charles F (2015) Polytocus focus: Uterine position effect is dependent upon horn size. Int J Dev Neurosci 40:85-91
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
Bertrand, Sarah J; Hu, Calvin; Aksenova, Marina V et al. (2015) HIV-1 Tat and cocaine mediated synaptopathy in cortical and midbrain neurons is prevented by the isoflavone Equol. Front Microbiol 6:894
Moran, Landhing M; Fitting, Sylvia; Booze, Rosemarie M et al. (2014) Neonatal intrahippocampal HIV-1 protein Tat(1-86) injection: neurobehavioral alterations in the absence of increased inflammatory cytokine activation. Int J Dev Neurosci 38:195-203

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