Novel mechanisms of cocaine immune and brain compromise

Cocaine is an alkaloid and psychostimulant that has become an essential part of the world drug scene and is also the world’s most trafficked drug after cannabis (13-20 million users). Cocaine addiction is a worldwide public health issue and due to its short half-life and strong dopaminergic activity make it the most addictive of the psychostimulants. In the HIV-infected population, cocaine accelerates HIV progression and worsens HIV outcomes; however, whether these mechanisms are due to poor ART adherence, transient psychotic events, and irreversible long-term damage is unknown. The accepted mechanism of cocaine action is by enhancing the monoamine neurotransmitter (dopamine, serotonin, and norepinephrine) activity in the central and peripheral nervous system at the synaptic level by blocking the presynaptic reuptake of these neurotransmitters. However, recent data from several laboratories, including ours, demonstrate that cocaine strongly regulated histone methylation, expression, and localization of key transcription factors, open/closing DNA domains, gene expression, and dopaminylation. But it is unclear whether all these nuclear transcription regulations elicited by cocaine are mediated by dopamine receptors and transporters, especially in non-neuronal cells such as immune cells.
Our data indicate that: first, cocaine localized into the nucleus in non-neuronal cells; second, cocaine in leukocytes increased HIV replication, monocyte/lymphocyte differentiation, and related inflammation; third, cocaine effects on leukocytes are not due to dopamine/serotonin/NE dysregulation like in neurons; fourth, blocking D1/D2/DAT signaling did not prevent the cocaine activation of leukocytes, and lastly, cocaine compromise nuclear remodeling even in the absence of neurotransmitter signaling. We propose that cocaine induces immune activation and the role of nuclear cocaine in HIV and associated inflammation. Our hypothesis is that “cocaine in non-neuronal cells targets the nucleus directly changing transcription to accelerate leukocyte differentiation and HIV transcription.” We expect that identifying novel mechanisms of cocaine toxicity in the uninfected and HIV-infected population will provide additional tools to prevent and revert cocaine toxicity.