Investigating the Role of Orthodenticle Homeobox 2 in Alcohol Consumption

ABSTRACT: Alcohol use disorder (AUD) is a psychiatric disorder that involves the dysregulation of brain regions such as the ventral tegmental area (VTA). Orthodenticle homeobox 2 (OTX2) is a transcription factor that is important for the development of dopaminergic (DA) neurons residing in the VTA. Previous studies have demonstrated that ethanol exposure during development can reduce Otx2 mRNA levels in the central nervous system. In addition, transiently reducing OTX2 in the juvenile VTA has been implicated in the development of stress-induced depression in adults. Currently, nothing is known about the relationship between OTX2 and ethanol consumption. To investigate this, I tested whether binge drinking during adulthood would alter Otx2 mRNA and protein expression levels in the murine VTA. Binge drinking promoted an increase in both Otx2 mRNA and protein levels within the VTA. I next investigated whether RNA interference-induced knockdown of Otx2 within the adult murine VTA would alter binge-like ethanol consumption, and whether transient depletion of Otx2 in the juvenile VTA could impact ethanol consumption in adulthood. None of these manipulations affected ethanol drinking. However, transient reduction of Otx2 in the VTA of juvenile mice did increase tyrosine hydroxylase, an enzyme in the DA biosynthetic pathway, in the VTA and nucleus accumbens of adults. This is the first study to reveal that binge drinking during adulthood can impact Otx2 expression in the murine VTA, and that transiently reducing Otx2 in the VTA of juveniles can have a long-lasting effect on DA neurons.