Impact of cocaine, HIV and aging on calcium regulation of cortical neurons
Xiu-Ti Hu
Rush University Medical Center, USA
: J Forensic Toxicol Pharmacol
Abstract
Cocaine is a highly-addictive psychostimulant that affects cognition. Despite combination antiretroviral therapy (cART), mild forms of HIV-Associated Neurocognitive Disorders (HAND) are still prevalent and are expected to increase with the aging HIV+ population. HIV-infected cocaine abusers display more severe progression of HAND than non-abusing HIV/ AIDS patients. The medial prefrontal cortex (mPFC) is a regulator of addiction and neurocognition and is altered profoundly by chronic cocaine/HIV exposure in vivo. Mechanisms underlying mPFC neuronal dysregulation by cocaine/HAND are not fully understood, especially during aging but dysregulated neuronal Ca2+ homeostasis may play a critical role. Our studies focus on the effects of chronic cocaine, HIV and aging on voltage-gated Ca2+ channel (VGCC) function in mPFC pyramidal neurons, using cocaine-exposure and/or the HIV-1 transgenic (Tg) rat model. We perform electrophysiology (whole-cell patch-clamping) in brain slices to assess neuronal excitability and Ca2+ influx via VGCCs (represented by Ca2+ spikes) as well as biochemical studies (Western blotting) to evaluate changes in VGCC protein levels. We found that (1) Firing of mPFC pyramidal neurons is abnormally-increased and associated with excessive Ca2+ influx (which is toxic) via VGCCs in adolescent (~7 weeks-old) cocaine-exposed rats or HIV-1 Tg rats; (2) Similar neuronal/VGCC dysregulation occurs in young adult cocaine-exposed and/or HIV-1 Tg rats (6 month-old; 6mo), but some dysfunctions are significantly greater following combined exposure and (3) mPFC hyper-excitability remains in older (12 mo) HIV-1 Tg rats but with different mechanisms (unaltered voltage-sensitive Ca2+ influx associated with reduced L-channel protein levels). These findings reveal that mPFC excitability is altered by chronic cocaine, HIV and aging through different mechanisms. Besides Ca2+ dysregulation, our parallel studies also suggest that dysfunctional K+ channels also play a role in cocaine/HIV-induced mPFC hyperactivity. Together, our studies demonstrate that chronic exposure to cocaine/HIV in vivo significantly alters Ca2+ homeostasis in mPFC neurons, which could be exacerbated during aging.
Biography
Xiu-Ti Hu has his expertise in drug addiction and neuro-HIV research, which focuses on elucidating mechanisms that underlie neuronal dysfunction in the mesocorticolimbic dopamine system. He has published 58 peer-reviewed scientific articles and 10 invited book chapters.
Email: xiu-ti_hu@rush.edu
