Dataset Information

MTORC2 in the dorsomedial striatum of mice contributes to alcohol-dependent F-Actin polymerization, structural modifications, and consumption.

ABSTRACT: Actin is highly enriched at dendritic spines, and actin remodeling plays an essential role in structural plasticity. The mammalian target of rapamycin complex 2 (mTORC2) is a regulator of actin polymerization. Here, we report that alcohol consumption increases F-actin content in the dorsomedial striatum (DMS) of mice, thereby altering dendritic spine morphology in a mechanism that requires mTORC2. Specifically, we found that excessive alcohol consumption increases mTORC2 activity in the DMS, and that knockdown of Rictor, an essential component of mTORC2 signaling, reduces actin polymerization, and attenuates the alcohol-dependent alterations in spine head size and the number of mushroom spines. Finally, we show that knockdown of Rictor in the DMS reduces alcohol consumption, whereas intra-DMS infusion of the mTORC2 activator, A-443654, increases alcohol intake. Together, these results suggest that mTORC2 in the DMS facilitates the formation of F-actin, which in turn induces changes in spine structure to promote and/or maintain excessive alcohol intake.

SUBMITTER: Laguesse S

PROVIDER: S-EPMC5983552 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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mTORC2 in the dorsomedial striatum of mice contributes to alcohol-dependent F-Actin polymerization, structural modifications, and consumption.

Laguesse Sophie S Morisot Nadege N Phamluong Khanhky K Sakhai Samuel A SA Ron Dorit D

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20180207 7

Actin is highly enriched at dendritic spines, and actin remodeling plays an essential role in structural plasticity. The mammalian target of rapamycin complex 2 (mTORC2) is a regulator of actin polymerization. Here, we report that alcohol consumption increases F-actin content in the dorsomedial striatum (DMS) of mice, thereby altering dendritic spine morphology in a mechanism that requires mTORC2. Specifically, we found that excessive alcohol consumption increases mTORC2 activity in the DMS, and ...[more]

PMID: 29497165

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Project description:Excessive alcohol intake leads to mesostriatal neuroadaptations, and to addiction phenotypes. We recently found in rodents that alcohol increases fibroblast growth factor 2 (FGF2) expression in the dorsomedial striatum (DMS), which promotes alcohol consumption. Here, we show that systemic or intra-DMS blockade of the FGF2 receptor, FGF receptor-1 (FGFR1), suppresses alcohol consumption, and that the effects of FGF2-FGFR1 on alcohol drinking are mediated via the phosphoinositide 3 kinase (PI3K) signaling pathway. Specifically, we found that sub-chronic alcohol treatment (7 d × 2.5 g/kg, i.p.) increased Fgfr1 mRNA expression in the dorsal hippocampus and dorsal striatum. However, prolonged and excessive voluntary alcohol consumption in a two-bottle choice procedure increased Fgfr1 expression selectively in DMS. Importantly, systemic administration of the FGFR1 inhibitor PD173074 to mice, as well as its infusion into the DMS of rats, decreased alcohol consumption and preference, with no effects on natural reward consumption. Finally, inhibition of the PI3K, but not of the mitogen-activated protein kinase (MAPK) signaling pathway, blocked the effects of FGF2 on alcohol intake and preference. Our results suggest that activation of FGFR1 by FGF2 in the DMS leads to activation of the PI3K signaling pathway, which promotes excessive alcohol consumption, and that inhibition of FGFR1 may provide a novel therapeutic target for alcohol use disorder.SIGNIFICANCE STATEMENT Long-term alcohol consumption causes neuroadaptations in the mesostriatal reward system, leading to addiction-related behaviors. We recently showed that alcohol upregulates the expression of fibroblast growth factor 2 (FGF2) in dorsomedial striatum (DMS) or rats and mice, and in turn, FGF2 increases alcohol consumption. Here, we show that long-term alcohol intake also increases the expression of the FGF2 receptor, FGFR1 in the DMS. Importantly, inhibition of FGFR1 activity by a selective receptor antagonist reduces alcohol drinking, when given systemically or directly into the DMS. We further show that the effects of FGF2-FGFR1 on alcohol drinking are mediated via activation of the PI3K intracellular signaling pathway, providing an insight on the mechanism for this effect.

Dataset Information

MTORC2 in the dorsomedial striatum of mice contributes to alcohol-dependent F-Actin polymerization, structural modifications, and consumption.

Publications

mTORC2 in the dorsomedial striatum of mice contributes to alcohol-dependent F-Actin polymerization, structural modifications, and consumption.

Similar Datasets

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