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Activity-dependent neuroprotective protein (ADNP) is an alcohol-responsive gene and negative regulator of alcohol consumption in female mice.

ABSTRACT: Neuroadaptations in the brain reward system caused by excessive alcohol intake, lead to drinking escalation and alcohol use disorder phenotypes. Activity-dependent neuroprotective protein (ADNP) is crucial for brain development, and is implicated in neural plasticity in adulthood. Here, we discovered that alcohol exposure regulates Adnp expression in the mesolimbic system, and that Adnp keeps alcohol drinking in moderation, in a sex-dependent manner. Specifically, Sub-chronic alcohol treatment (2.5?g/kg/day for 7 days) increased Adnp mRNA levels in the dorsal hippocampus in both sexes, and in the nucleus accumbens of female mice, 24?h after the last alcohol injection. Long-term voluntary consumption of excessive alcohol quantities (~10-15?g/kg/24?h, 5 weeks) increased Adnp mRNA in the hippocampus of male mice immediately after an alcohol-drinking session, but the level returned to baseline after 24?h of withdrawal. In contrast, excessive alcohol consumption in females led to long-lasting reduction in hippocampal Adnp expression. We further tested the regulatory role of Adnp in alcohol consumption, using the Adnp haploinsufficient mouse model. We found that Adnp haploinsufficient female mice showed higher alcohol consumption and preference, compared to Adnp intact females, whereas no genotype difference was observed in males. Importantly, daily intranasal administration of the ADNP-snippet drug candidate NAP normalized alcohol consumption in Adnp haploinsufficient females. Finally, female Adnp haploinsufficient mice showed a sharp increase in alcohol intake after abstinence, suggesting that Adnp protects against relapse in females. The current data suggest that ADNP is a potential novel biomarker and negative regulator of alcohol-drinking behaviors.

SUBMITTER: Ziv Y

PROVIDER: S-EPMC6300527 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Activity-dependent neuroprotective protein (ADNP) is an alcohol-responsive gene and negative regulator of alcohol consumption in female mice.

Ziv Yarden Y Rahamim Nofar N Lezmy Noa N Even-Chen Oren O Shaham Ohad O Malishkevich Anna A Giladi Eliezer E Elkon Ran R Gozes Illana I Barak Segev S

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20180627 2

Neuroadaptations in the brain reward system caused by excessive alcohol intake, lead to drinking escalation and alcohol use disorder phenotypes. Activity-dependent neuroprotective protein (ADNP) is crucial for brain development, and is implicated in neural plasticity in adulthood. Here, we discovered that alcohol exposure regulates Adnp expression in the mesolimbic system, and that Adnp keeps alcohol drinking in moderation, in a sex-dependent manner. Specifically, Sub-chronic alcohol treatment ( ...[more]

PMID: 30008470

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Project description:BackgroundADNP is vital for embryonic development. Is this function conserved for the homologous protein ADNP2?ResultsDown-regulation/silencing of ADNP or ADNP2 in zebrafish embryos or mouse erythroleukemia cells inhibited erythroid maturation, with ADNP directly associating with the ?-globin locus control region.ConclusionADNPs are novel molecular regulators of erythropoiesis.SignificanceNew regulators of globin synthesis are suggested. Activity-dependent neuroprotective protein (ADNP) and its homologue ADNP2 belong to a homeodomain, the zinc finger-containing protein family. ADNP is essential for mouse embryonic brain formation. ADNP2 is associated with cell survival, but its role in embryogenesis has not been evaluated. Here, we describe the use of the zebrafish model to elucidate the developmental roles of ADNP and ADNP2. Although we expected brain defects, we were astonished to discover that the knockdown zebrafish embryos were actually lacking blood and suffered from defective hemoglobin production. Evolutionary conservation was established using mouse erythroleukemia (MEL) cells, a well studied erythropoiesis model, in which silencing of ADNP or ADNP2 produced similar results as in zebrafish. Exogenous RNA encoding ADNP/ADNP2 rescued the MEL cell undifferentiated state, demonstrating phenotype specificity. Brg1, an ADNP-interacting chromatin-remodeling protein involved in erythropoiesis through regulation of the globin locus, was shown here to interact also with ADNP2. Furthermore, chromatin immunoprecipitation revealed recruitment of ADNP, similar to Brg1, to the mouse ?-globin locus control region in MEL cells. This recruitment was apparently diminished upon dimethyl sulfoxide (DMSO)-induced erythrocyte differentiation compared with the nondifferentiated state. Importantly, exogenous RNA encoding ADNP/ADNP2 significantly increased ?-globin expression in MEL cells in the absence of any other differentiation factors. Taken together, our results reveal an ancestral role for the ADNP protein family in maturation and differentiation of the erythroid lineage, associated with direct regulation of ?-globin expression.

Dataset Information

Activity-dependent neuroprotective protein (ADNP) is an alcohol-responsive gene and negative regulator of alcohol consumption in female mice.

Publications

Activity-dependent neuroprotective protein (ADNP) is an alcohol-responsive gene and negative regulator of alcohol consumption in female mice.

Similar Datasets

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