Elucidating the role of ribosomal translation machinery in alcohol abuse disorders

Abstract

Alcohol abuse is a worldwide problem with concomitant medical, social and economic costs for which pharmacotherapeutic approaches are limited. As a result, most patients relapse within the first months of treatment (MILLER and HESTER, 1986; SINHA, 2011). In particular, cues that have been associated with alcohol can trigger alcohol-related memories, leading to craving and relapse to alcohol intake (SINHA, 2011). Therefore, prevention of relapse has been a major focus in drug development for alcohol abuse disorders (NEASTA et al., 2010; BARAK et al., 2013). mTORC1 is a signaling pathway that plays an important role in protein translation, synaptic plasticity and thus in learning and memory processes and may also contribute to neuroadaptations underlying alcohol abuse (NEASTA et al., 2014). Indeed, excessive alcohol drinking promotes mTORC1 activation and mTORC1-dependent protein translation in the nucleus accumbens (NAc) (NEASTA et a., 2010), a crucial brain region of the reward pathway (ROBINSON and BERRIDGE, 1993; NESTLER, 2002). The synaptic protein translation is controlled by mTORC1 through the phosphorylation and activation of downstream proteins. However, the role of mTORC1 downstream effectors-dependent synaptic proteins - the p70 ribosomal S6 kinase and the eukaryotic initiation factor 4E (eIF4E) and 4G (eIF4G) - in alcohol relapse remains largely unknown (HUYNH, SANTINI and KLANN, 2014). Thus, this project aims to determine whether S6 kinase inhibitor and the eukaryotic initiation factors 4E (eIF4E) and 4G (eIF4G) inhibitor (4EGI-1) in the NAc controls alcohol-seeking behavior and cue-induced reinstatement relapse in rat model of alcoholism. (AU)