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.
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.
|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) Evolution of the HIV-1 transgenic rat: utility in assessing the progression of HIV-1-associated neurocognitive disorders. J Neurovirol :|
|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|
|Fitting, Sylvia; McLaurin, Kristen A; Booze, Rosemarie M et al. (2017) 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|
|Javadi-Paydar, Mehrak; Roscoe Jr, Robert F; Denton, Adam R et al. (2017) HIV-1 and cocaine disrupt dopamine reuptake and medium spiny neurons in female rat striatum. PLoS One 12:e0188404|
|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|
|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|
|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|
|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; Booze, Rosemarie M; Mactutus, Charles F (2016) Progression of temporal processing deficits in the HIV-1 transgenic rat. Sci Rep 6:32831|
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