Interactions of neuroimmune signaling and glutamate plasticity in addiction

Abstract

Chronic use of drugs of abuse affects neuroimmune signaling; however, there are still many open questions regarding the interactions between neuroimmune mechanisms and substance use disorders (SUDs). Further, chronic use of drugs of abuse can induce glutamatergic changes in the brain, but the relationship between the glutamate system and neuroimmune signaling in addiction is not well understood. Therefore, the purpose of this review is to bring into focus the role of neuroimmune signaling and its interactions with the glutamate system following chronic drug use, and how this may guide pharmacotherapeutic treatment strategies for SUDs. In this review, we first describe neuroimmune mechanisms that may be linked to aberrant glutamate signaling in addiction. We focus specifically on the nuclear factor-kappa B (NF-κB) pathway, a potentially important neuroimmune mechanism that may be a key player in driving drug-seeking behavior. We highlight the importance of astroglial-microglial crosstalk, and how this interacts with known glutamatergic dysregulations in addiction. Then, we describe the importance of studying non-neuronal cells with unprecedented precision because understanding structure-function relationships in these cells is critical in understanding their role in addiction neurobiology. Here we propose a working model of neuroimmune-glutamate interactions that underlie drug use motivation, which we argue may aid strategies for small molecule drug development to treat substance use disorders. Together, the synthesis of this review shows that interactions between glutamate and neuroimmune signaling may play an important and understudied role in addiction processes and may be critical in developing more efficacious pharmacotherapies to treat SUDs.

Keywords: Addiction; Astroglia; Glutamate; Microglia; Neuroimmune.

Fig. 1

Hypothesized nucleus accumbens neuroimmune-glutamate interactions in addiction. Drugs of abuse (1) activate TLRs, which (2) triggers the NF-κB signaling pathway within microglial cells through activation of P38, which is expressed in activated microglia. Microglia then release pro-inflammatory cytokines such as TNFα and IL-1β. These cytokines then (3) bind to their receptors (TNFR, IL-1βR) on astroglia, which activates NF-κB through JNK pathways. Specifically, binding of these cytokines leads to activation of the IKK, c-Jun N-terminal kinase (JNK), and p38 MAPK, which leads to activation of the transcription factor NF-κB. This then leads to (4) repression of GLT-1 transcription and ultimately downregulation of the GLT-1 transporter, as TNFα negatively regulates EAAT2 transcription. Downregulation of GLT-1 protein results in an inability of astroglia to clear excess glutamate from the synapse during reinstated drug seeking (5). Following exposure to drug-associated cues, (6) glutamate release from cortical afferents into the nucleus accumbens is potentiated, leading to (7) activation of ionotropic glutamate receptors (e.g., AMPA, NMDA), rapid, transient post-synaptic plasticity, and relapse. In females, estrogen receptors (ERs) are located on various cell types including microglia and astroglia, and can directly inhibit NF-κB. TLR = toll-like receptor; P38 = p38 mitogen-activated protein kinase (MAPK); NF-κB = nuclear factor-kappa B; TNFα = tumor necrosis factor alpha; IL = interleukin; GLT-1 = glutamate transporter-1

Fig. 2

High-resolution 3-D image of an isolated Iba-1-positive microglia with orthogonal views. a Iba-1 labeling and modern confocal microscopy can be reliable used to label and image microglial syncytia (white). Within these syncytia, individual microglia (green) can be digitally isolated from neighboring cells and subsequently analyzed. b Here a space filling 3D render of the isolated microglia is shown (grey). This type of digital analyses can be used to obtain data for general physical parameters (surface area and volume). c Here the microglial cell of interest is shown (green) overlaid with a skeletonization (white). This type of analysis can be used to obtain structural characteristics (Sholl intersections, branch number, and branch order). Hashed boxes depict locations of inset panels. Scale bar depicts 10 μm