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