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.

Inhibition of FGF Receptor-1 Suppresses Alcohol Consumption: Role of PI3 Kinase Signaling in Dorsomedial Striatum

“…The qRT-PCR procedure was conducted as previously described (Even-Chen et al, 2017;Zipori et al, 2017;Ziv et al, 2019). Briefly, mice were killed by cervical dislocation.…”

“…After 1 week of habituation for individual housing, mice or rats were trained to consume alcohol in the intermittent access to 20% alcohol in twobottle choice (IA2BC) procedure as previously described (Warnault et al, 2013;Carnicella et al, 2014;Even-Chen et al, 2017;Ziv et al, 2019). Briefly, animals received three 24 h sessions of ad libitum access to two-bottle choice per week (tap water and 20% alcohol v/v) on Sundays, Tuesdays, and Thursdays, with 24 or 48 h of alcohol-deprivation periods between the alcohol-drinking sessions.…”

“…This procedure was conducted as previously described (Warnault et al, 2013;Even-Chen et al, 2017;Ziv et al, 2019). Training was similar to the IA2BC procedure as described, except that mice had access to sucrose (1% w/v) solution instead of alcohol, and training lasted 3 weeks before PD173074 treatment.…”

“…In these experiments, we tested the effects of alcohol exposure on Fgfr1 expression in several brain regions. The mRNA expression of Fgfr1 was normalized to Gapdh expression (Even-Chen et al, 2017;Zipori et al, 2017;Ziv et al, 2019), which we found to be unaffected by alcohol in the protocols we used (Even-Chen et al (2017)). Expression in each brain region was further normalized to the corresponding control group (saline-or water-treated group).…”

“…Finally, to assess whether the effects of PD173074 are because of general effects on reward or fluid consumption, we tested whether PD173074 affects sweetened solution consumption (sucrose 1%). Mice were trained to consume sucrose in the intermittent access two-bottle choice procedure for 3 weeks, as we previously described Ziv et al, 2019). PD173074 (15 mg/kg, i.p.)…”