Summavielle, TeresaCanedo, TeresaSilva, Ana IsabelAndrade, Elva BonifácioAlmeida, Tiago O.Bravo, JoanaTerceiro, Ana FilipaCanedo, TeresaSilva, Ana IsabelMagalhães, AnaRelvas, João B.Bonifácio Andrade, ElvaBravo, Joana2026-01-222026-01-222023-07Summavielle, T., Canedo, T., Silva, A. I., Andrade, E. B., Almeida, T., Bravo, J., Terceiro, A. F., Portugal, C. C., Socodato, R., Magalhães, A., & Relvas, J. B. (2023). Blockingmethamphetamine-induced microglia reactivity by targeting glutamate receptors. XVI European Meeting on Glial Cells in Health and Disease 2023 - Abstract booklet, Glia 71, E1063–E1064. https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.244190894-1491http://hdl.handle.net/10400.22/31593Exposure to psychostimulants has been classically associated with damage to neuronal terminals. However, it is now accepted that interaction between neuronal and glial cells also contributes to the addictive behavior. We have recently shown that acute methamphetamine (Meth), a powerful psychostimulant, causes microgliosis and increases microglia activation through astrocytic-TNF release1. We are now interested in clarifying the progression of neuroinflammation under chronic drug exposure and how different brain and immune cells contribute to this inflammatory process.To explore this, firstly, we performed a proteomic analysis, in different phases of the addictive process, in mice exposed to an escalating dosing of Meth for ten days (Meth10d). To validate the conditioning power of our model, mice were tested in a condition place preference (CPP) at 10d of Meth, and 2 or 10 days of withdrawal (WD). At all these time points, mice were seen to be strongly conditioned by Meth. Next, we conducted a proteomic analysis to compare the different time points (using the hippocampus, where we previously found robust microgliosis underMeth1). We found a proteome profile that varied substantially with exposure (Meth10d) and after a short- (WD2d)and long-term withdrawal (WD10d) periods. Interestingly, the most altered pathways were neuro transmitter-related.However, we also identified significant differences in Wnt signaling, which was previously linked to regulation of microglia reactivity. As such, we evaluated the microglia profile after chronic Meth exposure and at withdrawal. In the hippocampus, the number of microglia cells was significantly increased at Meth10d and remained also increased at WD2d. Microglia presented a more ameboid-like shape at Meth10d, but its ramified morphology was recovered at WD2d. Importantly, our proteomic data also revealed that during Meth withdrawal, several microglial receptors were down regulated, suggesting that microglia was in a “primed” state. In addition, as the crosstalk between neurons and microglia seems to be relevant for the behavioral expression of Meth, we are dissecting the modulation of microgliaby neurons under Meth exposure, to evaluate neuroimmune regulatory ligand-receptor pairs that seem to impact on the neuron-microglia interaction. Of note, some these ligand-receptor pairs seem to be down regulated by chronic Meth and during abstinence, which may be associated with reduced neuronal ability to down regulate microglia reactivity, and lead to increased neuronal damage. We fore see that these receptors may prove to be interesting therapeutic targets for the treatment of addiction, and therefore we will manipulate them to confirm their value in reducing relapse rates and improve addiction treatments.engMethamphetamine (Meth)Meth-induced TNFconference poster1098-1136