Cocaine-abusing, HIV+ individuals experience more severe and rapidly evolving neuropsychiatric disorders and HIV-associated neurocognitive disorders (HAND) than non-abusing HIV+ individuals. These disorders reflect in part, a dysregulation of the medial prefrontal cortex (mPFC), but the underlying mechanisms are unclear. To significantly advance understanding of this phenomenon, we submit this R21 application to implement a new rat model of the comorbid human condition wherein critical features of both HIV+ and cocaine abuse are emulated to investigate the functional state of mPFC neurons. The research objectives are: (1) To reveal dysfunction of the mPFC in non-infectious, young (10-12 week old) adult HIV-1 transgenic (Tg) rats that chronically express multiple HIV-1 protein toxins in the brain, but do not exhibit the overt pathologies seen in old Tg rats (i.e., 10-12 months of age). (2 To determine if an exaggerated pathophysiology exists in the mPFC of HIV-1 Tg rats trained to self-administer cocaine. Our central hypothesis is that mPFC pyramidal neurons are more prone to over-activation in cocaine self-administering Tg rats than in saline-treated Tg rats or cocaine self-administering non-Tg rats. We will test this hypothesis with two Specific Aims.
Aim 1 will validate [the level of microgliosis] in the mPFC, and determine their association with abnormally- enhanced neuronal excitability mediated via over-activated L-type Ca2+ channels in the young adult Tg rats. Non-Tg rats will serve as controls. Functional activity of mPFC pyramidal neurons will be assessed in ex vivo brain slices using patch-clamp recording techniques. We expect that the Tg rats will show [mPFC microgliosis] and hyper-excitability of pyramidal neurons mediated by over-activated L-channels, reflected by abnormally-increased responses to excitatory stimuli.
Aim 2 will determine that cocaine self- administration enhances the pyramidal cell pathophysiology seen in the Tg rats. We expect that cocaine will exacerbate the hyper-excitability of mPFC pyramidal neurons observed in the Tg rats. This research is significant and innovative because it will provide the first means to ascertain the functional consequences of the chronic brain exposure of HIV-1 proteins under conditions of cocaine self-administration;in so doing, it will provide a completely novel method to investigate the molecular and cellular mechanisms responsible for this comorbid condition. The outcomes expected by the end of two years will determine that the HIV-1 proteins-induced pathology and cocaine abuse converge to dysregulate mPFC neuronal function via over- activated L-channels. These outcomes will guide our future investigations on mechanisms underlying the dysregulated Ca2+ homeostasis in the mPFC. Thus, this bold research will vertically elevate our understanding of the mechanisms that may contribute to the neuropathogenesis of HAND and neuropsychiatric disorders associated with HIV+ and cocaine abuse. This new knowledge will also lead to a R01 application in which novel therapeutic strategies will be developed to reduce such pathology.

Public Health Relevance

The combination of cocaine abuse and AIDS accelerates the brain damage that can accompany either condition alone. Unfortunately, the frequency of this combination, or comorbidity, it is increasing in our society. This project will determine how toxic viral proteins produced by HIV in the rat brain, with or without cocaine self- administration, alter the function of neurons in a bran region (the medial prefrontal cortex) which, in humans, is vulnerable to both HIV infection and cocaine abuse. We propose that the detrimental effects of HIV toxins will be potentiated by cocaine on specific proteins that are critical for normal neuronal firing. By identifying common molecular targets of cocaine and HIV toxins, outcomes from this project should prove to be critically important in developing therapeutic means to slow the devastation of HIV/AIDS comorbidity with cocaine abuse, as well as to promote drug abstinence in these individuals.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DA033882-02
Application #
8507202
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Sorensen, Roger
Project Start
2012-07-15
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$220,320
Indirect Cost
$76,320
Name
Rush University Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
068610245
City
Chicago
State
IL
Country
United States
Zip Code
60612
Napier, T Celeste (2017) Impact on Cortical Function of Cocaine Abuse Co-Occurring with HIV. Neuropsychopharmacology 42:365
Wayman, Wesley N; Chen, Lihua; Hu, Xiu-Ti et al. (2016) HIV-1 Transgenic Rat Prefrontal Cortex Hyper-Excitability is Enhanced by Cocaine Self-Administration. Neuropsychopharmacology 41:1965-73
Hu, Xiu-Ti (2016) HIV-1 Tat-Mediated Calcium Dysregulation and Neuronal Dysfunction in Vulnerable Brain Regions. Curr Drug Targets 17:4-14
Khodr, Christina E; Chen, Lihua; Dave, Sonya et al. (2016) Combined chronic blockade of hyper-active L-type calcium channels and NMDA receptors ameliorates HIV-1 associated hyper-excitability of mPFC pyramidal neurons. Neurobiol Dis 94:85-94
Wayman, Wesley N; Chen, Lihua; Napier, T Celeste et al. (2015) Cocaine self-administration enhances excitatory responses of pyramidal neurons in the rat medial prefrontal cortex to human immunodeficiency virus-1 Tat. Eur J Neurosci 41:1195-206
Wayman, Wesley N; Chen, Lihua; Persons, Amanda L et al. (2015) Cortical consequences of HIV-1 Tat exposure in rats are enhanced by chronic cocaine. Curr HIV Res 13:80-7
Napier, T Celeste; Chen, Lihua; Kashanchi, Fatah et al. (2014) Repeated cocaine treatment enhances HIV-1 Tat-induced cortical excitability via over-activation of L-type calcium channels. J Neuroimmune Pharmacol 9:354-68
Sharma, Amit; Hu, Xiu-Ti; Napier, T Celeste et al. (2011) Methamphetamine and HIV-1 Tat down regulate ?-catenin signaling: implications for methampetamine abuse and HIV-1 co-morbidity. J Neuroimmune Pharmacol 6:597-607