The role of brainstem norepinephrine in binge alcohol drinking and taste aversion

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Abstract Frequent binge drinking, and common pattern of alcohol (ethanol) consumption across the lifespan, has been linked to numerous adverse consequences. Particularly concerning is the fact that regular binge drinking significantly increases an individual’s risk of developing ethanol dependence. Thus, it is a highly significant goal to identify neuronal mechanisms that modulate binge drinking as such knowledge will provide insight into novel pharmaceutical treatments to help curb binge drinking and which in turn may reduce the risk of progressing to more serious forms of alcohol use disorders (AUDs). Research aimed at the neurobiology of AUDs has focused considerable attention to the reinforcing effects of ethanol and how these effects motivate binge-like ethanol intake. Interestingly there is accumulating evidence that ethanol also entails aversive effects and that these effects, because they are clearly dose related, can act as a deterrent to overconsumption. Because the neurocircuitry underlying the aversive effects of ethanol is still poorly understood, in the last funding period we began to characterize the neuronal mechanisms that modulate the aversive reactions to ethanol and their role in modulating binge-like ethanol consumption. We found that binge-like ethanol drinking increases the activity of neurons in the A2 (caudal nucleus of the solitary tract; NTS) and A6 (locus coeruleus; LC) brainstem regions, two of the primary sources of norepinephrine (NE) that send afferent projections to numerous brain structures that modulate motivated behaviors. Interestingly, we discovered that chemogenetic activation of NE+ circuits from the LC to the rostromedial tegmental nucleus (RMTg) or the A2 to the lateral parabrachial nucleus (PBN), target regions that have been implicated in modulating the aversive properties of ethanol, significantly blunted binge-like ethanol intake in mice. Further, activating the NE+ LC  RMTg circuit induced unconditioned aversive behaviors in mice, and silencing this pathway attenuated ethanol-induced conditioned taste aversion (CTA). Our guiding hypothesis is that activation of these NE+ circuits trigger a protective mechanism to “break” ethanol intake by promoting aversive responses to ethanol. More recently, we observed NE circuits arising from the LC and A2 that directly innervate the ventral tegmental area (VTA), a brain region critical for modulating both reward and aversion. Surprisingly, there has been almost no investigation into the role of NE signaling in the VTA in the modulation of ethanol intake or the aversive properties of ethanol. Proposed experiments logically flow from the original grant but will significantly advance our understanding of the novel mechanisms under investigation by 1) revealing novel NE+ circuits that modulate binge-like ethanol intake and the aversive properties of ethanol, 2) identifying the adrenergic receptors (AR) that are involved, and 3) identifying neuroplastic changes in AR expression on specific populations of neurons in RMTg, PBN, and VTA resulting from repeated cycles of binge- like ethanol intake. As the mechanisms and NE circuits under investigation have received little attention with respect to neurobiological response to ethanol, the proposed studies are highly novel and innovative.