3 years ago

Region specific activation of the AKT and mTORC1 pathway in response to excessive alcohol intake in rodents

Region specific activation of the AKT and mTORC1 pathway in response to excessive alcohol intake in rodents
Nadege Morisot, Khanhky Phamluong, Sophie Laguesse, Dorit Ron
We previously reported that the kinase AKT is activated in the nucleus accumbens (NAc) of rodents in response to excessive consumption of alcohol. One of the important downstream targets of AKT is the mammalian Target Of Rapamycin in Complex 1 (mTORC1), which was also activated by alcohol intake. mTORC1 controls dendritic protein translation, and we showed that the mTORC1-dependent translational machinery is activated in the NAc in response to alcohol intake. Importantly, systemic or intra-NAc inhibition of the AKT/mTORC1 pathway attenuated alcohol-drinking behaviors. Here, we mapped the activation patterns of AKT and mTORC1 in corticostriatal regions of rodents consuming large amounts of alcohol. We found that the activation of AKT and mTORC1 in response to cycles of binge drinking of 20 percent alcohol was centered in the NAc shell. Both kinases were not activated in the dorsolateral striatum (DLS); however, AKT, but not mTORC1, was activated in the dorsomedial striatum (DMS) of mice but not rats. Interestingly, excessive intake of alcohol produced a selective activation of the AKT/mTORC1 pathway in the orbitofrontal cortex (OFC), which was not observed in medial prefrontal cortex (mPFC). Furthermore, this signaling pathway was not activated in the NAc shell or OFC of rats consuming moderate amounts of alcohol nor was it activated in rats consuming sucrose. Together, our results suggest that excessive alcohol intake produces a brain region selective activation of the AKT/mTORC1 pathway, which is likely to contribute to NAc shell and OFC-dependent mechanisms that underlie the development and maintenance of alcohol drinking behavior. Excessive alcohol intake, but not moderate alcohol or sucrose consumption, produces a brain region selective activation of the AKT/mTORC1 pathway in the nucleus accumbens shell and the orbitofrontal cortex of rodents, which is likely to contribute to local molecular mechanisms that underlie the development and maintenance of alcohol drinking behavior.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/adb.12464

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