Glial mechanisms underlying substance use disorders

Addiction is a devastating disorder that produces persistent maladaptive changes to the central nervous system, including glial cells. Although there is an extensive body of literature examining the neuronal mechanisms of substance use disorders, effective therapies remain elusive. Glia, particularly microglia and astrocytes, have an emerging and meaningful role in a variety of processes beyond inflammation and immune surveillance, and may represent a promising therapeutic target. Indeed, glia actively modulate neurotransmission, synaptic connectivity and neural circuit function, and are critically poised to contribute to addictive-like brain states and behaviors. In this review, we argue that glia influence the cellular, molecular, and synaptic changes that occur in neurons following drug exposure, and that this cellular relationship is critically modified following drug exposure. We discuss direct actions of abused drugs on glial function through immune receptors, such as Toll-like receptor 4, as well as other mechanisms. We highlight how drugs of abuse affect glia-neural communication, and the profound effects that glial-derived factors have on neuronal excitability, structure, and function. Recent research demonstrates that glia have brain region-specific functions, and glia in different brain regions have distinct contributions to drug-associated behaviors. We will also evaluate the evidence demonstrating that glial activation is essential for drug reward and drug-induced dopamine release, and highlight clinical evidence showing that glial mechanisms contribute to drug abuse liability. In this review, we synthesize the extensive evidence that glia have a unique, pivotal, and underappreciated role in the development and maintenance of addiction.