Drug addiction is a growing issue that currently has no FDA‐approved pharmacotherapy; therefore, the concern on how to treat this rapidly increasing problem. The neuroadaptation of neurotransmitter release and signal transduction results in changes in cognitive processes that make it harder for users to stop using the addictive drug. It is believed that restoration of cognition dysfunction may be an effective treatment for addiction. Recent studies in our NIDA‐supported “Center for the Neurobiology of Addiction Treatment” indicated that the cognitive remediator LY379268, an mGluR2/3 agonist, is able to reverse self‐administration of cocaine in rats (Karkhanis, Beveridge, Blough, Jones, & Ferris, 2016, Drug and Alcohol Dependence, 166, 51–60). We hypothesized that the mechanism of LY379268 is to alter cellular signaling in parts of the brain critical for cognition. To test this hypothesis, we examined changes in cellular signal transduction, determined as mGluR2/3‐mediated Gi/o protein activation and the phosphorylation of extracellular‐regulated kinase 1 and 2 (ERK1/2) and cyclic AMP response element binding protein (CREB) in specific regions of the brain related to drug addiction and cognitive processes. Groups of Sprague‐Dawley rats were treated with acute or chronic dosing of LY379268 via subcutaneous Alzet minipump that released 1mg/kg of LY379268 for 36 hours or 14 days, respectively. The control group was subjected to the surgical procedure but did not have a pump inserted. After sacrifice, frozen brain sections were examined for LY379268‐stimulated [35S]GTPgammaS binding, and densities were quantitated in identified brain regions. Immunohistochemistry was performed in intervening sections to quantitate changes in phosphorylation levels using primary antibodies to phospho‐ or total CREB or ERK1/2, and secondary antibodies coupled to infrared dyes. The stained brain sections were imaged and densities were analyzed for those same brain regions that responded to LY379268 in G protein activation studies using LiCor Odyssey software. We observed that desensitization of the G protein‐coupled receptor resulted after the chronic treatment with LY379268. We also observed an increase in CREB phosphorylation in chronic compared with acute treatment but there were no differences between groups in ERK phosphorylation. These studies suggest that chronic treatment with an mGluR2/3 agonist results in sustained neurochemical changes that might be responsible for behavioral modifications seen in chronically‐treated animals.Support or Funding InformationNIDA grant P50‐DA006634This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.