Sir2/Sirt1 Links Acute Inebriation to Presynaptic Changes and the Development of Alcohol Tolerance, Preference, and Reward

Abstract

Acute ethanol inebriation causes neuroadaptive changes in behavior that favor increased intake. Ethanol-induced alterations in gene expression, through epigenetic and other means, are likely to change cellular and neural circuit function. Ethanol markedly changes histone acetylation, and the sirtuin Sir2/SIRT1 that deacetylates histones and transcription factors is essential for the rewarding effects of long-term drug use. The molecular transformations leading from short-term to long-term ethanol responses mostly remain to be discovered. We find that Sir2 in the mushroom bodies of the fruit fly Drosophila promotes short-term ethanol-induced behavioral plasticity by allowing changes in the expression of presynaptic molecules. Acute inebriation strongly reduces Sir2 levels and increases histone H3 acetylation in the brain. Flies lacking Sir2 globally, in the adult nervous system, or specifically in the mushroom body ␣/␤-lobes show reduced ethanol sensitivity and tolerance. Sir2-dependent ethanol reward is also localized to the mushroom bodies, and Sir2 mutants prefer ethanol even without a priming ethanol pre-exposure. Transcriptomic analysis reveals that specific presynaptic molecules, including the synaptic vesicle pool regulator Synapsin, depend on Sir2 to be regulated by ethanol. Synapsin is required for ethanol sensitivity and tolerance. We propose that the regulation of Sir2/SIRT1 by acute inebriation forms part of a transcriptional program in mushroom body neurons to alter presynaptic properties and neural responses to favor the development of ethanol tolerance, preference, and reward.

Mef2 induction of the immediate early gene Hr38/Nr4a is terminated by Sirt1 to promote ethanol tolerance

“…5 Briefly, groups of 20 genetically identical flies (n = 1) were exposed to 55% ethanol vapor or 100% humidified air, and the number of flies that lost the righting reflex were counted at 6 minutes intervals. 5 Briefly, groups of 20 genetically identical flies (n = 1) were exposed to 55% ethanol vapor or 100% humidified air, and the number of flies that lost the righting reflex were counted at 6 minutes intervals.…”

Genetics and genomics of alcohol responses in Drosophila

“…Tl , cact , MyD88 , imd , rel , and Spn27a ) as ethanol responsive, and recently Troutwine et al , (2016) tested each step in the Toll pathway and showed an effect on sensitivity but not tolerance. Similarly, Sirt1 , shown to be important for tolerance, was also flagged by Morozova et al , (2006), functionally tested by Kong et al , (2010a), and later extensively studied by Engel et al , (2016). An important general observation was that gene modules associated with innate ethanol sensitivity and tolerance were distinct (Morozova et al , 2009; Morozova et al , 2011; Morozova et al , 2014).…”

“…The mammalian homolog of Sir2 is called SIRT1 . Engel et al , (2016) described Sir2 ’s effect on alcohol responses in detail. Sir2 mutations perturb normal ethanol resistance, tolerance, and preference.…”

NMDAR dependent intracellular responses associated with cocaine conditioned place preference behavior

“…Specifically, SIRTs are enzymes that play a role in the modification chromatin structure, which leads to long-term epigenetic changes in gene transcription and expression [26] [27]. Recent evidence suggests that an increase in SIRT1/2 subtypes enhances the rewarding effects of cocaine [25] and mediates drug-induced neuroplasticity.…”

“…Recent evidence suggests that an increase in SIRT1/2 subtypes enhances the rewarding effects of cocaine [25] and mediates drug-induced neuroplasticity. NAc SIRT 1 and 2 protein levels increase following cocaine administration [28] and Resveratrol (a SIRT1 and 2 agonist) increases the rewarding effects of cocaine [26]. Local inhibition of SIRT1 and SIRT2 in the NAc decreases cocaine reward exemplified by attenuated CPP [28].…”