Brain Molecules under the Influence: Intracellular Regulation of Behavioral Responses Induced by Ethanol

Alcohol abuse is a devastating condition affecting millions of individuals. Regulation of insulin receptor (InR) signaling is critical for ethanol-induced responses and consumatory ethanol behavior. However, the precise intracellular mechanisms regulating InR signaling, which in turn, affect ethanol-induced behaviors remain unknown. I describe an InR/Arf6/S6K pathway that controls acute ethanol responses in Drosophila. I show that Arf6 mutants are hypersensitive to ethanol's intoxicating effects, and that Arf6 is specifically required in the adult nervous system to regulate na•ve ethanol sensitivity. While Arf6 functionally integrates activated Rac1 to the InR signaling, neuronal S6K, an InR effector, is a key mediator of Arf6-dependent regulation of ethanol-induced behaviors. Ethanol vapor concentrations that produce moderate sedation increase S6K-P, while doses that confer total sedation completely abate S6K-P. Arf6 mutants are completely devoid of neuronal S6K-P at baseline, suggesting that lack of S6K-P pre-sensitizes Arf6 mutants to the intoxicating effects of ethanol, and thus sedate at low physiologic ethanol concentrations. Because Arf6 has been implicated in receptor-mediated endocytosis, and signal transduction pathways are largely regulated by receptor trafficking, I propose a model in which Arf6 regulates InR signaling via endocytosis to control behavioral ethanol responses.
My doctoral work on the intracellular mechanisms that govern ethanol's intoxicating effects on behavior will be described. The present dissertation is divided in four main sections: 1) Introduction, 2) results and methods, which include figures and figure legends and 3) a discussion of the results. In the introduction, I will review the scientific literature on the regulatory mechanisms of ethanol-driven behaviors performed in humans and other vertebrate species, while the central focus of this thesis is on Drosophila research. In doing so, I will also highlight current issues and problems concerning the study of ethanol's direct and candidate targets, which affect behavioral responses to ethanol. In the result and methods section, I will describe my obtained experimental data and the methodology employed. In the discussion section, I will first illustrate on the initial part of the results dealing with neuronal Rac1, Arfip, and Arf6, which through a linear genetic pathway regulate acute ethanol sedation. Second, I will explain how Arf6 GTPase may integrate the Rho to InR signaling to control behavioral ethanol responses. Third, I will illuminate on recent data showing that Arf6 via neuronal S6K mediates behavioral sensitivity to ethanol. Moreover, I will propose a model in which Arf6 plays separable but intertwined roles in InR signaling and endocytosis, in order to regulate acute ethanol behaviors.