AbstractWe previously found that the brain‐derived neurotrophic factor (BDNF) in the dorsolateral striatum (DLS) is part of a homeostatic pathway that gates ethanol self‐administration [Jeanblancet al. (2009).J Neurosci,29, 13494–13502)]. Specifically, we showed that moderate levels (10%) of ethanol consumption increaseBDNFexpression within theDLS, and that direct infusion ofBDNFinto theDLSdecreases operant self‐administration of a 10% ethanol solution.BDNFbinding to its receptor, TrkB, activates the mitogen‐activated protein kinase (MAPK), phospholipase C‐γ (PLC‐γ) and phosphatidylinositol 3‐kinase (PI3K) pathways. Thus, here, we set out to identify which of these intracellular pathway(s) plays a role in the regulation of ethanol consumption byBDNF. We found that inhibition of theMAPK, but notPLC‐γ orPI3K, activity blocks theBDNF‐mediated reduction of ethanol consumption. As activation of theMAPKpathway leads to the initiation of transcription and/or translation events, we tested whether theBDNF‐mediated reduction of ethanol self‐administration requiresde novoprotein synthesis. We found that the inhibitory effect ofBDNFon ethanol intake is blocked by the protein synthesis inhibitor cycloheximide. Together, our results show thatBDNFattenuates ethanol drinking via activation of theMAPKpathway in a protein synthesis‐dependent manner within theDLS.