AMPK signaling in the nucleus accumbens core mediates cue-induced reinstatement of cocaine seeking

Gao, Xuejiao; Yuan, Kai; Cao, Lu; Yan, Wei; Luo, Yunping; Jian, Min; Liu, Jianfeng; Fang, Qin; Wang, Ji‐Shi; Han, Ying; Shi, Jie; Lü, Lin

doi:10.1038/s41598-017-01043-5

Cited by 20 publications

(32 citation statements)

References 73 publications

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“…p70S6k then phosphorylates ribosomal protein s6 (s6), a component of the 40S subunit of the ribosome (Chung et al, 1992). Changes in p70s6k have been reported following intraperitoneal cocaine injections (Sutton and Caron, 2015; but see Bailey et al, 2012), CPP (Yu et al, 2013;Shi et al, 2014), and cue-induced reinstatement Gao et al, 2017). Here, we found a modest trend toward increased p-p70s6k (Thr389) levels in the cocaine group compared with saline controls (Fig.…”

Section: Incubation Of Craving and Mtor-related Signalingsupporting

confidence: 59%

“…Nonetheless, our results point to an important role for specific translation pathways in the expression of incubation. mTOR pathway mTOR signaling is implicated in animal models of cocaine addiction (Neasta et al, 2014), including sensitization (Wu et al, 2011;Bailey et al, 2012), CPP (Bailey et al, 2012Yu et al, 2013;, and measures of motivation or relapse following cocaine self-administration James et al, 2014;Gao et al, 2017). In addition, mTOR regulates GluA1 expression (Slipczuk et al, 2009;Neasta et al, 2010;James et al, 2014James et al, , 2016 through local translation (Schratt et al, 2004;Beckley et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, ERK may have a general role in responding to cues, as discussed above for s6. Another study found increased ERK phosphorylation in NAc core after extinction of cocaine selfadministration, both before and after cue presentation leading to reinstatement (Gao et al, 2017).…”

Section: Erkmentioning

confidence: 97%

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Protein Translation in the Nucleus Accumbens Is Dysregulated during Cocaine Withdrawal and Required for Expression of Incubation of Cocaine Craving

et al. 2018

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Exposure to drug-associated cues can induce drug craving and relapse in abstinent addicts. Cue-induced craving that progressively intensifies ("incubates") during withdrawal from cocaine has been observed in both rats and humans. Building on recent evidence that aberrant protein translation underlies incubation-related adaptations in the NAc, we used male rats to test the hypothesis that translation is dysregulated during cocaine withdrawal and/or when rats express incubated cocaine craving. We found that intra-NAc infusion of anisomycin, a general protein translation inhibitor, or rapamycin, an inhibitor of mammalian target of rapamycin, reduced the expression of incubated cocaine craving, consistent with previous results showing that inhibition of translation in slices normalized the adaptations that maintain incubation. We then examined signaling pathways involved in protein translation using NAc synaptoneurosomes prepared after >47 d of withdrawal from cocaine or saline self-administration, or after withdrawal plus a cue-induced seeking test. The most robust changes were observed following seeking tests. Most notably, we found that eukaryotic elongation factor 2 (eEF2) and eukaryotic initiation factor 2α (eIF2α) are dephosphorylated when cocaine rats undergo a cue-induced seeking test; both effects are consistent with increased translation during the test. Blocking eIF2α dephosphorylation and thereby restoring its inhibitory influence on translation, via intra-NAc injection of Sal003 just before the test, substantially reduced cocaine seeking. These results are consistent with dysregulation of protein translation in the NAc during cocaine withdrawal, enabling cocaine cues to elicit an aberrant increase in translation that is required for the expression of incubated cocaine craving. Cue-induced cocaine craving progressively intensifies (incubates) during withdrawal in both humans and rats. This may contribute to persistent vulnerability to relapse. We previously demonstrated a role for protein translation in synaptic adaptations in the NAc closely linked to incubation. Here, we tested the hypothesis that translation is dysregulated during cocaine withdrawal, and this contributes to incubated craving. Analysis of signaling pathways regulating translation suggested that translation is enhanced when "incubated" rats undergo a cue-induced seeking test. Furthermore, intra-NAc infusions of drugs that inhibit protein translation through different mechanisms reduced expression of incubated cue-induced cocaine seeking. These results demonstrate that the expression of incubation depends on an acute increase in translation that may result from dysregulation of several pathways.

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Section: Incubation Of Craving and Mtor-related Signalingsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

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Protein Translation in the Nucleus Accumbens Is Dysregulated during Cocaine Withdrawal and Required for Expression of Incubation of Cocaine Craving

et al. 2018

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“…These results indicate that rapamycin‐mediated changes in conditioned reward and sensitized behavior do not likely involve a reversal of cocaine's effects upon mTOR signaling within corticolimbic regions, suggesting that rapamycin interacts with some other cocaine‐induced neuroadaptation(s), independent of the downstream targets of mTOR to exert its apparent ‘anti‐addictive' and ‘anti‐sensitizing' effects. A recent study showed that AMPK activity in the NAc core was critical for the cue‐induced reinstatement of cocaine seeking, which might be mediated by mTORC1 and ERK1/2 signaling . Consistent with these studies, our results revealed that AMPK was activated following cocaine treatment.…”

Section: Discussionsupporting

confidence: 91%

Activation of AMPK‐dependent autophagy in the nucleus accumbens opposes cocaine‐induced behaviors of mice

Xiao

Deng

et al. 2019

Addiction Biology

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Cocaine is a strong central nervous system stimulant, which can induce drug addiction. Previous studies have reported that cocaine-induced autophagy is involved in neuroinflammation and cell death. However, the role of autophagy in psychomotor sensitivity to cocaine has not been explored. Here, we reported that D 1 receptor -CaMKII-AMPK-FoxO3a signaling pathway was involved in acute cocaine application-induced autophagy in the nucleus accumbens (NAc) both in vitro and in vivo. Furthermore, we found that knockdown of the ATG5 gene in the NAc augmented behavioral response to cocaine, and induction of autophagy in the NAc with rapamycin attenuated cocaine-induced behavioral response, which was coincident with the alterations of dendritic spine density in neurons of NAc. These results suggest that cocaine exposure leads to the induction of autophagy, which is a protective mechanism against behavioral response to cocaine of male mice.

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“…In addition, changes in mTOR signaling have been suggested to play an etiological role in the pathology of schizophrenia 60 . Given that mTOR represents one of the main effector pathways via which AMPK connects bioenergetic fluctuations to changes in synaptic transmission 43,44,61 and neurodevelopment 47,48 , we propose that targeting the AMPK-mTOR signaling axis might represent a novel therapeutic approach in schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

Kinase network dysregulation in a human induced pluripotent stem cell model of DISC1 schizophrenia

et al. 2019

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Protein kinases orchestrate signal transduction pathways involved in central nervous system functions ranging from neurodevelopment to synaptic transmission and plasticity. Abnormalities in kinase-mediated signaling are involved in the pathophysiology of neurological disorders, including neuropsychiatric disorders. Here, we expand on the hypothesis that kinase networks are dysregulated in schizophrenia. We investigated changes in serine/threonine kinase activity in cortical excitatory neurons differentiated from induced pluripotent stem cells (iPSCs) from a schizophrenia patient presenting with a 4-bp mutation in the disrupted in schizophrenia 1 (DISC1) gene and a corresponding control. Using kinome peptide arrays, we demonstrate large scale abnormalities in DISC1 cells, including a global depression of serine/threonine kinase activity, and changes in activity of kinases, including AMP-activated protein kinase (AMPK), extracellular signal-regulated kinases (ERK), and thousand-and-one amino acid (TAO) kinases. Using isogenic cell lines in which the DISC1 mutation is either introduced in the control cell line, or rescued in the schizophrenia cell line, we ascribe most of these changes to a direct effect of the presence of the DISC1 mutation. Investigating the gene expression signatures downstream of the DISC1 kinase network, and mapping them on perturbagen signatures obtained from the Library of Integrated Network-based Cellular Signatures (LINCS) database, allowed us to propose novel drug targets able to reverse the DISC1 kinase dysregulation gene expression signature. Altogether, our findings provide new insight into abnormalities of kinase networks in schizophrenia and suggest possible targets for disease intervention.

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AMPK signaling in the nucleus accumbens core mediates cue-induced reinstatement of cocaine seeking

Cited by 20 publications

References 73 publications

Protein Translation in the Nucleus Accumbens Is Dysregulated during Cocaine Withdrawal and Required for Expression of Incubation of Cocaine Craving

Protein Translation in the Nucleus Accumbens Is Dysregulated during Cocaine Withdrawal and Required for Expression of Incubation of Cocaine Craving

Activation of AMPK‐dependent autophagy in the nucleus accumbens opposes cocaine‐induced behaviors of mice

Kinase network dysregulation in a human induced pluripotent stem cell model of DISC1 schizophrenia

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