This NRSA application is submitted for support of my PhD training in an individualized, integrated program involving pharmacology, neurobiology of substance abuse and HIV immunology. Drug abuse contributes to one-third of all HIV infections in the US. Corticostriatal systems of the brain are damaged in HIV-infected individuals and in those that abuse cocaine. There is no FDA-approved pharmacotherapy for cocaine abuse, and current antiretroviral therapy for AIDs does not prevent CNS pathogenesis, including HIV-associated neurocognitive disorders (HAND). HIV-1 proteins (e.g., Tat, a transactivator of transcription) released in the CNS result in cellular dysregulation and toxicity, in part, by an excessive increase in cytosolic Ca2+ levels. We recently identified an over-activation of the L-type Ca2+ channels in the medial prefrontal cortex (mPFC) as a potential site where the consequences of Tat and cocaine exposure may overlap. The current research project will verify this possibility. Glutamatergic pyramidal neurons within the mPFC are critical regulators of cognition and reward-mediated behaviors, including seeking for cocaine and relapse to drug-taking;two behaviors that preclude successful cocaine abuse rehabilitation. Clinical observations reveal that HIV+ individuals who abuse cocaine exhibit more rapidly evolving HAND, with associated neurotoxicity, and may be more resistant to current behavioral/cognitive therapy for addiction. To better understand this co-morbidity, I plan to use a self-administering rat model of cocaine abuse and relapse to test the central hypotheses that (i) mPFC exposure to Tat enhances cocaine-seeking, and (ii) this effect is associated with the ability of Tat to enhance the effects of self-administered cocaine on L-type Ca2+ channels activity in mPFC pyramidal neurons. The planned studies will contribute to my overall NRSA objective to acquire outstanding training in neuropharmacology and immunology, and to become an expert at state-of-the-art behavioral, electrophysiological and anatomical techniques. Accordingly, I propose two Specific Aims to be conducted in rats self-administering cocaine (a technique I've already acquired).
Specific Aim 1 : To ascertain if pyramidal neurons in the mPFC taken from these rats exhibit potentiated excitatory responses to in vitro applications of Tat which are mediated by L-type Ca2+ channels. For these studies, I will learn whole cell patch clamping techniques in forebrain slices.
Specific Aim 2 : To determine if injections of Tat directly into the mPFC of cocaine-administering rats will enhance reactivity to cocaine-associated cues (a measure of cocaine seeking), to ascertain the neuropathology associated with this effect, and whether it can be blocked by L-type channel antagonists. Outcomes from this research will help us to better understand the neurophysiological mechanisms of dysfunctional mPFC Ca2+ homeostasis in HIV+ individuals co-morbid with cocaine addiction. The training experiences will help assure that I complete my PhD, present and publish the work, and locate an exceptional post doctoral position in the field.
The proposed research is relevant to public health and advances NIH's mission because it will identify a converging mechanism in early HIV-1 infection and cocaine abuse as a risk factor for neuronal dysfunction and drug relapse. Completion of the proposed studies will move the field vertically by providing the mechanistic overlap of cocaine abuse and HIV-1 viral protein, Tat, neurotoxicity, thus allowing in the identification of possible protective therapies to be given during early withdrawal and beyond to impede further neuropathology in these individuals.
|Hu, Xiu-Ti (2016) HIV-1 Tat-Mediated Calcium Dysregulation and Neuronal Dysfunction in Vulnerable Brain Regions. Curr Drug Targets 17:4-14|
|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|
|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|
|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; Dodiya, Hemraj B; Persons, Amanda L et al. (2012) Enduring cortical alterations after a single in-vivo treatment of HIV-1 Tat. Neuroreport 23:825-9|