Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

Abstract

Drugs of abuse cause persistent alterations in synaptic plasticity that may underlie addiction behaviors. Evidence suggests glial cells have an essential and underappreciated role in the development and maintenance of drug abuse by influencing neuronal and synaptic functions in multifaceted ways. Microglia and astrocytes perform critical functions in synapse formation and refinement in the developing brain, and there is growing evidence that disruptions in glial function may be implicated in numerous neurological disorders throughout the lifespan. Linking evidence of function in health and under pathological conditions, this review will outline the glial and neuroimmune mechanisms that may contribute to drug-abuse liability, exploring evidence from opioids, alcohol, and psychostimulants. Drugs of abuse can activate microglia and astrocytes through signaling at innate immune receptors, which in turn influence neuronal function not only through secretion of soluble factors (eg, cytokines and chemokines) but also potentially through direct remodeling of the synapses. In sum, this review will argue that neural-glial interactions represent an important avenue for advancing our understanding of substance abuse disorders.

Figure 1

Glia modify synaptic plasticity via secreted factors, synapse formation, and synaptic pruning. (a) Synaptic elements from neurons are engulfed by microglia, which can alter synaptic circuitry. (b) Secreted factors from microglia and neurons include chemokines and cytokines. This allows for communication between different cell types (eg, neuronal expressed IL-34 can bind to microglial CSF1R). Blue represents neuronal origin, while green represents microglial origin. (c) Synapse formation via astrocytes (in purple) is positively and negatively regulated by hevin (yellow spheres) and SPARC (blue spheres), respectively. Astrocytes can also modulate neuronal activity through their effects on glutamate receptor trafficking and synaptic glutamate reuptake via GLT-1 and GLAST. (d) Synaptic pruning can occur in the CNS through a complement-mediated mechanism. C1q and C3 expressed on synapses can induce microglial engulfment and phagocytosis of synaptic elements. Within figure citations: ¹, Trotta et al, 2014; ², Lee and Kim, 2007; ³, Li et al, 2010a;⁴, Ginhoux et al, 2010; ⁵, Lin et al, 2008; ⁶, Chung et al, 2015a; ⁷, Clarke and Barres, 2013; ⁸, Schafer et al, 2012; ⁹, Stevens et al, 2007.

Figure 2

TLR4 signaling mechanisms. Many molecules including some drugs of abuse can activate TLR4. TLR4 is unique in that it produces MyD88-dependent and MyD88-independent pathway signaling. TLR4, Toll-like receptor 4.