Impact on Cortical Function of Cocaine Abuse Co-Occurring with HIV

According to the USA Center for Disease Control (http://www.cdc.gov/) over 36 million humans are currently living with HIV infection, with 44？000 new infections diagnosed annually in the USA, often reflecting risky sexual behavior. Substance use disorders (SUD) negatively influence every stage of the HIV/AIDS crisis, and SUD are a major obstacle in combating this global pandemic. Other than marijuana, cocaine is the most frequently abused illicit drug in HIV adults (eg, Martin et al., 2016). Cocaine use is associated with increased likelihood of engaging in risky sex, accelerated disease progression, and non-adherence to antiretroviral treatment. An emerging explanation for this association relates to impulsive decision-making. While both cocaine-abusing and HIV-infected individuals often score higher on cognitive impulsivity tasks, those with the comorbidity tend to show the greatest impulsivity (eg, Martin et al, 2016 and references therein). Human imaging studies point to impairments in prefrontal–subcortical networks in these deficits (eg, Meade et al, 2011). To capture a more mechanistic view and to help identify potential therapeutic targets, my laboratory recently set out to evaluate neuropathophysiology within the medial prefrontal cortex (mPFC) in the context of HIV/AIDS comorbidity. We focused on the principal outputs, ie, pyramidal neurons. As we recently reviewed (Wayman et al, 2015), our initial studies demonstrated that acute exposure to a prominent HIV-1 neurotoxic protein, Tat, induced an enduring mPFC astrogliosis and hyper excitability of mPFC pyramidal neurons that was exacerbated by chronic cocaine exposure. These effects were mediated by over-activation of high-voltage-activated L-type calcium channels and were associated with a Tat-induced increase expression of a calcium channel pore-forming protein, Cav1.2-α1c. To better generalize the phenomenon to the chronic nature of brain exposure to HIV-1 proteins, we subsequently evaluated mPFC pathophysiology in HIV-1 transgenic rats following cocaine self-administration. As predicted by Tat-mediated excitotoxicity, the transgenic rats exhibited enhanced mPFC Cav1.2-α1c expression, and a pyramidal cell hyper excitability and excitotoxicity (Wesley et al, 2016). This dysregulation was exacerbated following 2 weeks of withdrawal from cocaine self-administration (Wesley et al., 2016)