Period 2 Gene Deletion Abolishes β-Endorphin Neuronal Response to Ethanol

Background:  Ethanol exposure during early life has been shown to permanently alter the circadian expression of clock regulatory genes and the β‐endorphin precursor proopiomelanocortin (POMC) gene in the hypothalamus. Ethanol also alters the stress‐ and immune‐regulatory functions of β‐endorphin neu...

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Published in:Alcoholism, clinical and experimental research clinical and experimental research, 2010-09, Vol.34 (9), p.1613-1618
Main Authors: Agapito, Maria, Mian, Nadia, Boyadjieva, Nadka I., Sarkar, Dipak K.
Format: Article
Language:English
Subjects:
Alcoholism and acute alcohol poisoning
Animals
Animals, Newborn
beta-Endorphin - metabolism
Biological and medical sciences
Cells, Cultured
Central Nervous System
Clock Gene
Endogenous Opioid
Ethanol
Ethanol - pharmacology
Female
Gene Deletion
Hypothalamus - drug effects
Hypothalamus - metabolism
Male
Medical sciences
Mice
Mice, Inbred C57BL
Neurons - metabolism
Period Circadian Proteins - genetics
Period Circadian Proteins - physiology
Stress Axis
Toxicology
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Summary:Background:  Ethanol exposure during early life has been shown to permanently alter the circadian expression of clock regulatory genes and the β‐endorphin precursor proopiomelanocortin (POMC) gene in the hypothalamus. Ethanol also alters the stress‐ and immune‐regulatory functions of β‐endorphin neurons in laboratory rodents. Our aim was to determine whether the circadian clock regulatory Per2 gene modulates the action of ethanol on β‐endorphin neurons in mice. Methods:  Per2 mutant (mPer2Brdml) and wild type (C57BL/6J) mice were used to determine the effect of Per2 mutation on ethanol‐regulated β‐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 β‐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). Results:  Per2 mutant mice showed a higher basal level of β‐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 β‐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 β‐endorphin levels to acute and chronic ethanol challenges in vivo. Conclusions:  These results suggest for the first time that the Per2 gene may be critically involved in regulating β‐endorphin neuronal function. Furthermore, the data revealed an involvement of the Per2 gene in regulating β‐endorphin neuronal responses to ethanol.
ISSN:0145-6008
1530-0277
DOI:10.1111/j.1530-0277.2010.01246.x