Cocaine Self-administration and Extinction Inversely Alter Neuron to Glia Exosomal Dynamics in the Nucleus Accumbens

Abstract

Alteration of glutamatergic synaptic plasticity in the Nucleus Accumbens (NAc) has been implicated in cocaine-seeking behaviors. Astroglial mechanisms for maintaining extracellular glutamate homeostasis through cysteine/glutamate exchanger (xCT) and glutamate transporter GLT1 are dysregulated following cocaine exposure and contribute to altered glutamatergic synaptic plasticity. However, how these astroglial proteins become dysregulated in cocaine addiction remains unknown. We recently showed that neuron to astroglial exosome signaling is essential to maintain GLT1 protein expression by transferring neuronal miR-124-3p into astrocytes to suppress GLT1-inhibiting microRNAs (miRs) in astrocytes. In the current study, by selectively labeling neuronal exosomes using CD63-GFP f/+ exosome reporter mice, we examined how the self-administration and extinction stages of the mouse cocaine self-administration model alter neuronal exosome signaling to astrocytes and microglia in the NAc. We found that cocaine (but not food) self-administration strongly reduces the internalization of neuronal exosomes, particularly in astrocytes in the NAc (but not in motor cortex), which can be effectively reversed by extinction training. In parallel, cocaine self-administration alone specifically and differentially affects activation of glial cells by decreasing GFAP expression in astrocytes but increasing Iba1 expression in microglia. However, extinction training fully reverses the increased Iba1 expression in microglia but only partially reverses the reduction of GFAP in astrocytes. Taken together, our study reveals altered in vivo dynamics of NAc neuronal exosomes in the cocaine addiction model, providing new insights about how altered neuron to glial exosome signaling may contribute to astroglial dysfunction in cocaine addiction.

Cocaine Self-Administration and Abstinence Modulate NMDA Receptor Subunits and Active Zone Proteins in the Rat Nucleus Accumbens

“…Cocaine enhances dopaminergic synaptic transmission by blockade of the dopamine transporter (DAT), which in turn leads to elevation of extracellular dopamine levels in the nucleus accumbens [31]. In our previous study, it was also shown that cocaine self-administration elevated extracellular accumbal dopamine levels during last cocaine session, whereas it did not affect basal accumbal dopamine levels [20].…”

Effects of Cocaine on Human Glial-Derived Extracellular Vesicles

“…Cocaine induced EV regulation involves the sigma 1 receptor (Sig-1R), ADP ribosylation factor 6 (ARF6) and myosin light chain kinase ( Machado-Pineda et al, 2018 ) but still remains poorly understood. Cocaine self-administration was shown to alter the signaling of neuronal exosomes to astrocytes using a CD63 reporter ( Jarvis et al, 2019 ). However, no studies have investigated the role of cocaine on extracellular vesicular proteins in human microglia.…”

Role of Inflammasomes in HIV-1 and Drug Abuse Mediated Neuroinflammaging

“…Therefore, understanding their role in HIV-1-induced aging will be an important area of research that warrants investigation. It has been reported that cocaine self-administration in mice reduced uptake of NDEVs by the astrocytes primarily in the motor cortex, an effect that was effectively reversed by extinction training [ 205 ]. Drugs of abuse like cocaine, morphine, methamphetamine [ 206 , 207 , 208 ] can induce chronic low-level inflammation and can also potentiate inflammatory status in the context of HIV-1 [ 209 , 210 , 211 ], which together can contribute to the process of inflammaging.…”