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Ethanol exposure during early life has been shown to permanently alter the circadian expression of clock regulatory genes and the beta-endorphin precursor proopiomelanocortin (POMC) gene in the hypothalamus. Ethanol also alters the stress- and immune-regulatory functions of beta-endorphin neurons in laboratory rodents. Our aim was to determine whether the circadian clock regulatory Per2 gene modulates the action of ethanol on beta-endorphin neurons in mice.Per2 mutant (mPer2(Brdml)) and wild type (C57BL/6J) mice were used to determine the effect of Per2 mutation on ethanol-regulated beta-endorphin neuronal activity during neonatal period using an in vitro mediobasal hypothalamic (MBH) cell culture model and an in vivo milk formula feeding animal model. The beta-endorphin neuronal activity following acute and chronic ethanol treatments was evaluated by measuring the peptide released from cultured cells or peptide levels in the MBH tissues, using enzyme-linked immunosorbent assay (ELISA).Per2 mutant mice showed a higher basal level of beta-endorphin release from cultured MBH cells and a moderate increase in the peptide content in the MBH in comparison with control mice. However, unlike wild type mice, Per2 mutant mice showed no stimulatory or inhibitory beta-endorphin-secretory responses to acute and chronic ethanol challenges in vitro. Furthermore, Per2 mutant mice, but not wild type mice, failed to show the stimulatory and inhibitory responses of MBH beta-endorphin levels to acute and chronic ethanol challenges in vivo.These results suggest for the first time that the Per2 gene may be critically involved in regulating beta-endorphin neuronal function. Furthermore, the data revealed an involvement of the Per2 gene in regulating beta-endorphin neuronal responses to ethanol.