The neuroimmune-glutamate hypothesis of addiction.

Addictive drugs impact corticostriatal glutamate signaling and have immunomodulatory effects which may underlie drug-associated behaviors during different phases of the addiction cycle. Here we hypothesize that glutamate dyshomeostasis induced by addictive drug use and withdrawal is heavily orchestrated by the neuroimmune system. We systematically define how drug-induced pathologies within the nucleus accumbens (NA) glutamate tripartite synapse are tightly regulated by neuroimmune signaling. Targets within the neuroimmune system represent a novel approach that can be leveraged for clinical studies with immunomodulatory therapeutics to reverse neurobiological changes induced by addictive drugs, and thus meaningfully reduce negative clinical outcomes relevant to substance use disorders (SUDs). We outline a novel hypothesis that control of a newly defined neuroimmune-glutamate circuit and inflammasome is heavily dependent upon the type of addictive drug as well as on phase of the addiction cycle. We further provide translational evidence underscoring the tenet that neuroimmunomodulation by addictive drugs functions according to an opponent process, and we outline predictions of our opponent process hypothesis when applied to relevant polysubstance use patterns in people who use drugs. This framework could be strategically leveraged in the experimental design of clinical studies of novel SUD therapeutics.