Neurodrinking: is alcohol a substrate in a novel, endogenous synthetic pathway for norepinephrine?

A number of preclinical and clinical studies indicate multiple types of interaction between ethanol intake and the mood-related neurotransmitter, norepinephrine (NE). For example, ethanol interacts with dopamine beta-hydroxylase (DBH), an enzyme that plays an essential role in the only well-established endogenous synthetic pathway for NE, whereby dopamine is hydroxylated to form NE. While the DBH pathway may indeed be the only endogenous mechanism for producing NE, another possibility is that multiple means have evolved for the biosynthesis of this very important neurotransmitter, where some pathways may be independent of DBH. If so, such redundancy would provide greater assurance that enough NE is available for the body to use in this neurotransmitter's various physiological roles. This paper puts forth the hypothesis ethanol is a substrate in a novel, endogenous synthetic pathway for NE, consistent with some studies showing that intake of ethanol increases the concentration of endogenous NE. Also consistent with this hypothesis, the molecular structure of ethanol is a physical subset of the structure of NE itself. If the hypothesis is correct, it may have important implications for understanding the physiological basis of alcohol use, abuse, and dependence in humans, as well as modeling these phenomena in animals. Importantly, the hypothesis is directly testable in rodents by presenting ethanol to DBH knockout mice, which are thought to lack NE, and then measuring if NE is synthesized in these animals.