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 #
5R01DA013137-14
Application #
8588907
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
2013-12-01
Budget End
2014-11-30
Support Year
14
Fiscal Year
2014
Total Cost
$326,250
Indirect Cost
$101,250
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; Illenberger, Jessica M; McLaurin, Kristen A et al. (2018) Identification of Dopamine D1-Alpha Receptor Within Rodent Nucleus Accumbens by an Innovative RNA In Situ Detection Technology. J Vis Exp :
McLaurin, Kristen A; Booze, Rosemarie M; Mactutus, Charles F (2018) Evolution of the HIV-1 transgenic rat: utility in assessing the progression of HIV-1-associated neurocognitive disorders. J Neurovirol 24:229-245
Bertrand, Sarah J; Mactutus, Charles F; Harrod, Steven B et al. (2018) HIV-1 proteins dysregulate motivational processes and dopamine circuitry. Sci Rep 8:7869
Mohseni Ahooyi, Taha; Shekarabi, Masoud; Torkzaban, Bahareh et al. (2018) Dysregulation of Neuronal Cholesterol Homeostasis upon Exposure to HIV-1 Tat and Cocaine Revealed by RNA-Sequencing. Sci Rep 8:16300
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
McLaurin, Kristen A; Li, Hailong; Booze, Rosemarie M et al. (2018) Unraveling Individual Differences In The HIV-1 Transgenic Rat: Therapeutic Efficacy Of Methylphenidate. Sci Rep 8:136
McLaurin, Kristen A; Booze, Rosemarie M; Mactutus, Charles F (2017) Temporal processsing demands in the HIV-1 transgenic rat: Amodal gating and implications for diagnostics. Int J Dev Neurosci 57:12-20
McLaurin, Kristen A; Moran, Landhing M; Li, Hailong et al. (2017) A Gap in Time: Extending our Knowledge of Temporal Processing Deficits in the HIV-1 Transgenic Rat. J Neuroimmune Pharmacol 12:171-179
McLaurin, Kristen A; Booze, Rosemarie M; Mactutus, Charles F (2017) Selective developmental alterations in The HIV-1 transgenic rat: Opportunities for diagnosis of pediatric HIV-1. J Neurovirol 23:87-98
McLaurin, Kristen A; Booze, Rosemarie M; Mactutus, Charles F et al. (2017) Sex Matters: Robust Sex Differences in Signal Detection in the HIV-1 Transgenic Rat. Front Behav Neurosci 11:212

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