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

Abstract

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% 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.

Prosapip1-Dependent Synaptic Adaptations in the Nucleus Accumbens Drive Alcohol Intake, Seeking, and Reward

“…To test for brain region specificity, we measured the level of the protein in the two other striatal regions, the dorsomedial striatum (DMS) and the dorsolateral striatum (DLS). In line with the observation that alcohol does not activate mTORC1 in the DMS and DLS (Laguesse et al, 2016), Prosapip1 levels were unaltered by alcohol in either striatal regions (Figures S2D and S2E). Together, these data suggest that the translation of Prosa-pip1 is selectively induced in the NAc in response to chronic intermittent consumption of high levels of alcohol.…”

“…Rapamycin did not alter the total mRNA levels of Prosapip1 in the presence or absence of alcohol (Figure S1B), indicating that alcohol induced an increase in Prosapip1 translation without a change at the transcriptional level. In addition, rapamycin, even at a high dose (40 mk/kg), did not alter the translation of Prosapip1 in water-only-consuming animals (Figure S1C), suggesting that long-term alcohol intake that activates mTORC1 in the NAc (Laguesse et al, 2016; Neasta et al, 2010) is a prerequisite for mTORC1-dependent translation of Prosapip1.…”

“…However, also in contrast to Uys et al findings and ours, Spiga et al reported that alcohol-dependent rats undergoing withdrawal exhibit loss of thin spines in the NAc core, without alteration of mushroom-like spines (Spiga et al, 2014). We found that mTORC1 activation is localized to the NAc shell and is not observed in the NAc core or the DMS (Laguesse et al, 2016). The three striatal regions participate differentially in the mechanisms underlying alcohol seeking (Cor-bit et al, 2012, 2016).…”

“…We previously found that excessive alcohol consumption activates the PI3K/AKT pathway in the nucleus accumbens (NAc) of rodents resulting in the activation of mTORC1 (Beckley et al, 2016; Laguesse et al, 2016; Liu et al, 2017; Neasta et al, 2010). We further demonstrated that intra-NAc or systemic administration of the selective mTORC1 inhibitors attenuates alcohol seeking and drinking (Beckley et al, 2016; Neasta et al, 2010; Morisot et al, 2017).…”

Alcohol‐dependent molecular adaptations of the NMDA receptor system

“…Specifically, we showed that acute systemic administration of alcohol as well as episodes of heavy alcohol drinking activates mTORC1 in the NAc shell of rodents (Laguesse et al . 2016; Neasta et al . ).…”