There is a consistent correlation between rodent populations that voluntarily consume more ethanol in a two bottle choice assay and increased operant oral self administration of ethanol [33]. Because oral self administration of ethanol stimulates dopamine release [34], it is possible that the unc-79 gene product acts in the ventral tegmental area (VTA) to mediate or modulate NALCN function. In dopaminergic VTA neurons, neurotensin and other neuromodulators activate a nonselective cationic conductance with properties similar to the NALCN channel [18]. Furthermore, a neurotensin- and substance P-activated inward sodium current is absent from cultured NALCN knockout VTA neurons [13]. It is possible that ethanol acts directly upon NALCN channels in the VTA to influence firing rate. Alternatively, ethanol might alter the release of neurotensin, substance P, or other neuromodulators in the VTA to influence NALCN/unc-79 function secondarily. Testing of these hypotheses in the future may lead to insight into the mechanism of action of ethanol on the nervous system and specifically into mechanisms of reward-related behavior.
