Re-exposure to nicotine-associated context from adolescence enhances alcohol intake in adulthood

Zipori, Dor; Sadot-Sogrin, Yossi; Goltseker, Koral; Even-Chen, Oren; Rahamim, Nofar; Shaham, Ohad; Barak, Segev

doi:10.1038/s41598-017-02177-2

Cited by 19 publications

(15 citation statements)

References 57 publications

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“…The dorsal striatum is divided into two anatomical and functional subregions: the DMS and the DLS. The DMS is implicated in goal-directed behavior (Yin et al, 2005;Yin and Knowlton, 2006) and is important for the early stages of alcohol consumption (Corbit et al, 2012). The DLS is implicated in habit learning .…”

Section: The Effect Of Excessive Alcohol Consumption On Fgf2 Expressimentioning

confidence: 99%

“…*p Ͻ 0.05; # p ϭ 0.09. (White and McDonald, 2002;Featherstone and McDonald, 2004;Yin et al, 2004) and in compulsive alcohol/drug consumption (Everitt and Robbins, 2005;Corbit et al, 2012). Because we found that excessive voluntary alcohol intake led to upregulation of Fgf2 expression in the dorsal striatum (Fig.…”

Section: The Effect Of Excessive Alcohol Consumption On Fgf2 Expressimentioning

confidence: 99%

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Fibroblast Growth Factor 2 in the Dorsomedial Striatum Is a Novel Positive Regulator of Alcohol Consumption

et al. 2017

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Repeated alcohol intake leads to mesostriatal neuroadaptations, resulting in drinking escalation and addiction phenotypes. Fibroblast growth factor 2 (FGF2) has been shown to interact with the mesostriatal dopaminergic system, and has been implicated in the actions of psychostimulants in the brain, and in several psychiatric disorders. Here, we report on a positive regulatory feedback loop of alcohol and FGF2 in rodent models. Specifically, we found that acute alcohol exposure (2.5 g/kg, i.p.) increased the mRNA expression of in the dorsal hippocampus, nucleus accumbens, and dorsal striatum. Longer alcohol exposure (7 d × 2.5 g/kg, i.p.) restricted these increases to the dorsal striatum, and the latter effect was blocked by the dopamine D2-like receptor antagonist haloperidol. Voluntary prolonged and excessive alcohol consumption in a 2-bottle choice procedure increased expression selectively in dorsomedial striatum (DMS) of both mice and rats. Importantly, we found that systemic administration of recombinant FGF2 (rFGF2) in mice, or rFGF2 infusion into the dorsal striatum or DMS of rats, increased alcohol consumption and preference, with no similar effects on saccharin or sucrose consumption. Finally, we found that inhibition of the endogenous FGF2 function in the DMS, by an anti-FGF2 neutralizing antibody, suppressed alcohol consumption and preference. Together, our results suggest that alcohol consumption increases the expression of in the DMS, and that striatal FGF2 promotes alcohol consumption, suggesting that FGF2 in the DMS is a positive regulator of alcohol drinking. Long-term alcohol intake may lead to neuroadaptations in the mesostriatal reward system, resulting in addiction phenotypes. Fibroblast growth factor 2 (FGF2) is crucial for the development and maintenance of the mesostriatal dopaminergic system. Here, we provide evidence for the involvement of FGF2 in alcohol-drinking behaviors. We show that alcohol increases expression in the dorsal striatum, an effect mediated via dopamine D2-like receptors. Importantly, we show that infusion of recombinant FGF2 into the dorsomedial striatum increases alcohol consumption, whereas inhibiting the endogenous FGF2 function suppresses consumption. Thus, FGF2 is an alcohol-responsive gene constituting a positive regulatory feedback loop with alcohol. This loop leads to facilitation of alcohol consumption, marking FGF2 as a potential new therapeutic target for alcohol addiction.

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Section: The Effect Of Excessive Alcohol Consumption On Fgf2 Expressimentioning

confidence: 99%

Section: The Effect Of Excessive Alcohol Consumption On Fgf2 Expressimentioning

confidence: 99%

Fibroblast Growth Factor 2 in the Dorsomedial Striatum Is a Novel Positive Regulator of Alcohol Consumption

et al. 2017

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“…Adnp expression was normalized to Gapdh expression [7,8,29]. Importantly, we recently showed that Gapdh levels are not affected in mice under the alcohol drinking protocols used here [7].…”

Section: Discussionmentioning

confidence: 99%

“…Mice were euthanized, and brains were quickly removed and placed on an ice-cold platform. Tissues from the NAc, dorsal hippocampus and VTA were carefully dissected from 1-mm slices using a brain matrix and immediately snap-frozen in liquid nitrogen and stored at −80°C until use for further analysis for qRT-PCR, as previously described [7,29].…”

Section: Tissue Collectionmentioning

confidence: 99%

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

Ziv

Rahamim

Lezmy

et al. 2018

Neuropsychopharmacol

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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.

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“…Interestingly, a recent study showed that the reexposure to a context previously associated with nicotine caused a 50 percent reduction in Gdnf expression in the VTA, coupled with pronounced and long-lasting (3 month) increases in operant alcohol selfadministration and relapse (Zipori et al 2017). These findings suggest that breakdown of the GDNF pathway is a common adaptation that may underlie co-morbidity of nicotine and alcohol misuse.…”

Section: Gdnf Is a Negative Regulator Of Alcohol Intakementioning

confidence: 99%

GDNF and alcohol use disorder

et al. 2018

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Glial cell line-derived neurotrophic factor (GDNF) has been extensively studied for its role in the development and maintenance of the midbrain dopaminergic system, although evidence suggests that GDNF also plays a role in drug and alcohol addiction. This review focuses on the unique actions of GDNF in the mechanisms that prevent the transition from recreational alcohol use to abuse. Specifically, we describe studies in rodents suggesting that alcohol acutely increases GDNF expression in the ventral tegmental area, which enables the activation of the mitogen-activated protein kinase signaling pathway and the gating of alcohol intake. We further provide evidence to suggest that GDNF acts in the ventral tegmental area via both nongenomic and genomic mechanisms to suppress alcohol consumption. In addition, we describe findings indicating that when this endogenous protective pathway becomes dysregulated, alcohol intake levels escalate. Finally, we describe the potential use of GDNF inducers as a novel therapeutic approach to treat alcohol use disorder.

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Re-exposure to nicotine-associated context from adolescence enhances alcohol intake in adulthood

Cited by 19 publications

References 57 publications

Fibroblast Growth Factor 2 in the Dorsomedial Striatum Is a Novel Positive Regulator of Alcohol Consumption

Fibroblast Growth Factor 2 in the Dorsomedial Striatum Is a Novel Positive Regulator of Alcohol Consumption

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

GDNF and alcohol use disorder

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