Molecular mechanisms underlying alcohol-drinking behaviours

Ron, Dorit; Barak, Segev

doi:10.1038/nrn.2016.85

Cited by 163 publications

(186 citation statements)

References 216 publications

(304 reference statements)

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“…However, in light of our findings and previous conflicting reports on the role of the CeA in defensive behavior (Cai et al, 2014; Koo et al, 2004; LeDoux et al, 1988; Li et al, 2013), further studies will be required to resolve how, if at all, defensive behaviors are positively mediated by the pathway from the CeA to PAG. Nevertheless, the involvement of several distinct CeA projection neurons as positive mediators of appetitive behavior validates the integral role of the CeA in reward-related function (Badrinarayan et al, 2012; Gallagher and Chiba, 1996; Gallagher et al, 1990; Knapska et al, 2006; Parkinson et al, 2000; Ron and Barak, 2016). …”

Section: Discussionmentioning

confidence: 59%

Basolateral to Central Amygdala Neural Circuits for Appetitive Behaviors

Kim

Zhang

Muralidhar

et al. 2017

Neuron

380

493

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Summary Basolateral amygdala (BLA) principle cells are capable of driving and antagonizing behaviors of opposing valence. BLA neurons project to the central amygdala (CeA), which also participates in negative and positive behaviors. However, the CeA has primarily been studied as the site for negative behaviors and the causal role for CeA circuits underlying appetitive behaviors is poorly understood. Here we identified several genetically distinct populations of CeA neurons that mediate appetitive behaviors and dissected the BLA to CeA circuit for appetitive behaviors. Protein phosphatase 1 regulatory subunit 1B+ BLA pyramidal neurons to dopamine receptor 1+ CeA neurons define a pathway for promoting appetitive behaviors, while R-spondin 2+ BLA pyramidal neurons to dopamine receptor 2+ CeA neurons define a pathway for suppressing appetitive behaviors. These data reveal genetically defined neural circuits in the amygdala that promote and suppress appetitive behaviors analogous to the direct and indirect pathway of the basal ganglia.

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Section: Discussionmentioning

confidence: 59%

Basolateral to Central Amygdala Neural Circuits for Appetitive Behaviors

Kim

Zhang

Muralidhar

et al. 2017

Neuron

380

493

View full text Add to dashboard Cite

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“…A growing number of studies in recent years have started to elucidate specific neuroadaptations that underlie the development and maintenance of excessive alcohol seeking and drinking in brain region specific manner (Ron and Barak, 2016), our findings that the AKT/mTORC1 pathway is activated by alcohol in very restricted brain regions paves the way for future studies on the role of the pathway in these corticostriatal brain regions.…”

Section: Discussionmentioning

confidence: 69%

“…It would be of interest to test the activation of AKT/mTORC1 signaling pathway after a longer period of abstinence. Furthermore, one of the main upstream kinases activated by alcohol is protein kinase A (PKA) (Ron and Barak, 2016) and we previously provided findings that link the AKT/mTORC1 to PKA signaling in the NAc (Beckley et al, 2016; Ben Hamida et al, 2012), and thus it is plausible that the recruitment of PKA signaling in the NAc shell and OFC in response to repeated cycles of binge alcohol intake initiates the activation of the AKT/mTORC1 pathway.…”

Section: Discussionmentioning

confidence: 99%

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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“…p75NTR localization in the DLS is altered in rats with a history of excessive alcohol drinking and withdrawal As described above, the beneficial actions of BDNF to reduce alcohol self-administration are abolished after repeated cycles of binge drinking and withdrawal. It is well established that chronic alcohol intake produces molecular adaptations that contribute to the development or maintenance of alcohol-drinking behaviors (Ron and Barak, 2016). We therefore hypothesized that longterm exposure to alcohol alters BDNF/TrkB signaling in the DLS.…”

Section: Bdnf In the Dls Does Not Alter Alcohol Consumption In Rats Wmentioning

confidence: 99%

The Neurotrophic Factor Receptor p75 in the Rat Dorsolateral Striatum Drives Excessive Alcohol Drinking

et al. 2016

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Brain-derived neurotrophic factor (BDNF) signaling in the dorsolateral striatum (DLS) keeps alcohol intake in moderation. For example, activation of the BDNF receptor tropomyosin receptor kinase B (TrkB) in the DLS reduces intake in rats that consume moderate amounts of alcohol. Here, we tested whether long-term excessive consumption of alcohol produces neuroadaptations in BDNF signaling in the rat DLS. We found that BDNF was no longer able to gate alcohol self-administration after a history of repeated cycles of binge alcohol drinking and withdrawal. We then elucidated the possible neuroadaptations that could block the ability of BDNF to keep consumption of alcohol in moderation. We report that intermittent access to 20% alcohol in a two-bottle choice paradigm that models excessive alcohol drinking produces a mobilization of DLS p75 neurotrophin receptor (p75NTR), whose activities oppose those of the Trk receptors, including TrkB. These neuroadaptations were not observed in the DLS of rats exposed to continuous access to 10% alcohol or in rats consuming sucrose. Furthermore, short hairpin RNA (shRNA)-mediated knockdown of the p75NTR gene in the DLS, as well as intra-DLS infusion or systemic administration of the p75NTR modulator, LM11A-31, significantly reduced binge drinking of alcohol. Together, our results suggest that excessive alcohol consumption produces a change in BDNF signaling in the DLS, which is mediated by the recruitment of p75NTR. Our data also imply that modulators of p75NTR signaling could be developed as medications for alcohol abuse disorders.

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Molecular mechanisms underlying alcohol-drinking behaviours

Cited by 163 publications

References 216 publications

Basolateral to Central Amygdala Neural Circuits for Appetitive Behaviors

Basolateral to Central Amygdala Neural Circuits for Appetitive Behaviors

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

The Neurotrophic Factor Receptor p75 in the Rat Dorsolateral Striatum Drives Excessive Alcohol Drinking

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