Investigations into the neurobiology of substance use disorders (SUD) have historically focused on neurons. However, recent years have brought a notable shift toward recognition of contributions of nonneuronal cells to SUDs. Here, we provide a brief overview of this emerging topic and suggest future research directions.
Drug effects on glial cells
Accumulating evidence indicates that drug exposure can have dynamic and long-lasting effects on glial cells in the brain, including astrocytes, microglia, and oligodendrocytes. Among the first reported effects of rodent drug self-administration on astrocytes was decreased expression of mediators of glutamate homeostasis in the nucleus accumbens following self-administration of cocaine, heroin, nicotine, and ethanol. Using the membrane-associated Lck-GFP fluorescent reporter, more recent studies indicate that extinction from cocaine self-administration is associated with reduction of structural properties and synaptic co-localization of astrocytes in the nucleus accumbens , further suggesting adverse effects of contingent cocaine exposure on neuron–astrocyte communication.
Inflammatory glial responses are also observed following drug use, particularly following chronic opiate treatments associated with tolerance and hyperalgesia. For example, upregulation of proinflammatory cytokines and toll-like receptor signaling on microglia and astrocytes is associated with these processes. However, engagement of these pathways following self-administration has remained less clear. Notably, recent reports demonstrate that self-administration of cocaine also leads to activation of microglia within the reward circuitry [2, 3]. Likewise, consequences of drug self-administration on oligodendrocytes are largely unknown. While there have been reports on effects of drug use on myelination and white matter integrity, detailed consequences to structure and activity of oligodendrocytes remain obscure. Intriguingly, a recent transcriptome analysis within the prefrontal cortex of male rats revealed upregulation of markers of oligodendrocyte maturation and differentiation following heroin self-administration .
Roles of glial cells in behaviors associated with SUD
Beyond the effects of drugs on properties of nonneuronal cells, a growing number of investigations have also assessed the functional contributions of glial cells to behaviors associated with SUDs. For example, ligand stimulation of astrocyte-specific Gq DREADD receptors in the nucleus accumbens leads to reduced reinstatement to cocaine seeking . Further, VTA astrocytes drive avoidance behaviors via stimulation of GABAergic neurons, and stimulation of VTA astrocytes can block cocaine conditioned place preference . Selective overexpression of the oligodendrocyte precursor-specific protein, Sox10, in the prefrontal cortex decreases motivation to self-administer heroin . Future studies should evaluate whether and how oligodendrocyte activity elsewhere in the brain might influence drug taking or relapse. These results collectively suggest that manipulation of glial cells can alter drug-seeking behaviors, and in particular that stimulation of glial cells within the reward circuitry may in some cases oppose drug seeking.
In summary, accumulating evidence suggests that glial cells are critical players in the complex mechanisms of drug seeking, and may represent viable candidates for SUD treatment strategies. In order to identify new glia-based therapeutic targets, continued studies will be required to elucidate more complete glia-specific adaptations associated with SUD, and how amelioration of these adaptations can stem vulnerability to relapse.
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Funding and disclosure
Funding support provided by DHHS R01DA041455 (KJR) and R01DA041208, P50MH094268, and R01MH083728 (MVP). The authors declare that they have no conflict of interest.
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Reissner, K.J., Pletnikov, M.V. Contributions of nonneuronal brain cells in substance use disorders. Neuropsychopharmacol. 45, 224–225 (2020). https://doi.org/10.1038/s41386-019-0494-5