mTOR complex 1: a key player in neuroadaptations induced by drugs of abuse

Neasta, Jérémie; Barak, Segev; Hamida, Sami Ben; Ron, Dorit

doi:10.1111/jnc.12725

Cited by 105 publications

(109 citation statements)

References 117 publications

(237 reference statements)

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“…We previously observed that IA20%-2BC results in a robust and sustained activation of the AKT/mTORC1 pathway in the NAc of mice (Neasta et al, 2014; Neasta et al, 2011), results which were replicated herein (Fig. S1).…”

Section: Resultssupporting

confidence: 86%

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

et al. 2016

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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.

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Section: Resultssupporting

confidence: 86%

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

et al. 2016

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“…We show that excessive alcohol consumption increases the F-actin content in the NAc of mice, which is mediated through Prosapip1. As mTORC1 is activated by numerous drugs of abuse (Neasta et al, 2014), it is plausible that the mTORC1/Prosapip1 axis is a master regulator of drug-dependent actin dynamics.…”

Section: Discussionmentioning

confidence: 99%

“…mTORC1 phosphorylates the p70 ribosomal S6 kinase (S6K) and the eukaryotic translation initiation factor 4E binding protein (4E-BP), and these phosphorylation events promote the assembly of the translation initiation complex to initiate cap-dependent mRNA translation (Sonenberg and Hinnebusch, 2009). mTORC1 has been shown to be a focal point in mechanisms underlying the actions of drugs of abuse (Neasta et al, 2014). However, how mTORC1 signaling regulates synaptic functions, especially in the context of addiction, is not entirely clear.…”

Section: Introductionmentioning

confidence: 99%

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

Laguesse

Morisot

Shin

et al. 2017

Neuron

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SUMMARY The mammalian target of rapamycin complex 1 (mTORC1), a transducer of local dendritic translation, participates in learning and memory processes as well as in mechanisms underlying alcohol-drinking behaviors. Using an unbiased RNA-seq approach, we identified Prosapip1 as a novel downstream target of mTORC1 whose translation and consequent synaptic protein expression are increased in the nucleus accumbens (NAc) of mice excessively consuming alcohol. We demonstrate that alcohol-dependent increases in Prosapip1 levels promote the formation of actin filaments, leading to changes in dendritic spine morphology of NAc medium spiny neurons (MSNs). We further demonstrate that Prosapip1 is required for alcohol-dependent synaptic localization of GluA2 lacking AMPA receptors in NAc shell MSNs. Finally, we present data implicating Prosapip1 in mechanisms underlying alcohol self-administration and reward. Together, these data suggest that Prosapip1 in the NAc is a molecular transducer of structural and synaptic alterations that drive and/or maintain excessive alcohol use.

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“…Based on the evidence from the hippocampus for a specifi c role of mTORC1 in late forms of synaptic plasticity and in LTM, it is not surprising that mTORC1 contributes to the synaptic and behavioral effects observed in animal models of drug addiction. Here we describe several of the relevant studies, and we refer the reader to recent reviews for a more complete perspective on this very active fi eld of research (Neasta et al 2014 ;Dayas et al 2012 ).…”

Section: Mtor Signaling In Models Of Drug Addictionmentioning

confidence: 99%

mTOR and the Regulation of Translational Capacity in Late Forms of Synaptic Plasticity

Tsokas

Blitzer

2014

Synaptic Tagging and Capture

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Stimulus-induced changes in gene expression, mediated by translation and transcription, are required for persistent forms of synaptic plasticity (late-LTP and late-LTD) and for memory consolidation. In recent years, the search for the translational control mechanisms that operate during synaptic plasticity has centered on signaling within the dendritic compartment, guided by the accumulating evidence that proteins synthesized within dendrites, and not in the cell body, are required for late-LTP and late-LTD. Among the fi rst such control mechanisms to be discovered was the activation of mechanistic target of rapamycin (mTOR; formerly called mammalian TOR), a ubiquitous translational regulator that is required for the induction of late-LTP and late-LTD. The consistent requirement of mTOR in multiple forms of late plasticity suggests that it is involved in the synthesis of both LTPand LTD-related plasticity-related proteins (PRPs).This chapter focuses on the importance of mTOR-regulated translational capacity in neurons and other cells that must rapidly synthesize proteins in response to appropriate stimuli. The role of mTOR in synaptic plasticity, and the potential mechanisms by which synaptic activity activates mTOR, are addressed. We review the behavioral studies that established the relevance of mTOR to long-term memory (LTM), including the consolidation and reconsolidation of hippocampus-dependent LTM, and the acquisition and expression of drug-seeking behavior. Finally, we outline a model of synaptic capture in which activation of mTOR raises the

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mTOR complex 1: a key player in neuroadaptations induced by drugs of abuse

Cited by 105 publications

References 117 publications

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

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

mTOR and the Regulation of Translational Capacity in Late Forms of Synaptic Plasticity

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