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Background: - Alcohol-induced pro-inflammatory activation might influence cellular and synaptic pathology, thus contributing to the behavioral phenotypes associated with alcohol use disorders. In the present study, the possible anti-inflammatory properties of N-[(4-trifluoromethyl)-benzyl]4-methoxybutyramide (GET73), a promising therapeutic agent for alcohol use disorder treatment, were evaluated in primary cultures of rat cortical microglia. Methods: - Primary cultures of cerebral cortex microglial cells were treated with 100 ng/ml lipopolysaccharide (LPS; 8 h, 37 °C) or 75 mM ethanol (EtOH; 4 days, 37 °C) alone or in the presence of GET73 (1–30 µM). At the end of the incubation period, multiparametric quantification of cytokines/chemokines was performed by using the xMAP technology and Luminex platform. Furthermore, cultured microglial cell viability following the treatment with EtOH and GET73, alone or in combination, has been measured by a colorimetric assay (i.e. MTT assay). Results: - GET73 (10 and 30 µM) partially or fully prevented the LPS-induced increase of IL-6, IL-1β, RANTES/CCL5 protein and MCP-1/CCL2 levels. On the contrary, GET73 failed to attenuate the TNF-α level increase induced by LPS. Furthermore, GET73 treatment (10–30 µM) significantly attenuated or prevented the EtOH-induced increase of TNF-α, IL-6, IL-1β and MCP-1/CCL2 levels. Finally, at all the concentrations tested (1–30 µM), the GET73 treatment did not alter the EtOH-induced reduction of microglial cell viability. Conclusions: - The current results provide the first in vitro evidence of GET73 protective properties against EtOH-induced neuroinflammation. These data add more information on the complex and multifactorial profile of action of the compound, further supporting the significance of developing GET73 as a therapeutic tool for the treatment of individuals with alcohol use disorders.

In the present study, the effects of the ?-hydroxybutyrate (GHB) analog GET73 on hippocampal glutamate transmission have been evaluated by an approach combining in vivomicrodialysis with the in vitroevaluation of tissue slices. The microdialysis results indicated that local perfusion (60 min) with 10 nM-1 mM GET73 increased extracellular glutamate levels in the CA1 region of the hippocampus of freely moving rats in a concentration dependent manner. In tissue slices from the rat hippocampus, GET73 (1 µM - 10 µM) did not affect L-[3H]glutamate uptake, whereas treatment with 1 µM GET73 significantly increased K+-evoked, but not spontaneous, glutamate efflux. The GHB analog did not affect the increase in glutamate efflux induced by 100 µM and 300 µM NMDA. In contrast, 500 nM GET73, a concentration at which it is ineffective alone, partially but significantly counteracted the increase in K+-evoked glutamate efflux induced by 100 µM CHPG, an mGluR5 agonist. When 500 nM GET73 was coperfused with 100 µM MPEP, it amplified the decrease in K+-evoked glutamate efflux induced by the mGluR5 antagonist. Interestingly, the increase in K+-evoked glutamate efflux induced by 1 µM GET73 was counteracted by coperfusion with a low (10 µM) concentration of MPEP, which by itself is ineffective. Finally, 500 nM GET73 did not affect the reduction of K+-evoked glutamate efflux induced by the mGluR2/3 agonist LY379268.

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