mTOR regulates cocaine-induced behavioural sensitization through the SynDIG1–GluA2 interaction in the nucleus accumbens

Li, Hongchun; Zhang, Jiamei; Xu, Rui; Wang, Yonghai; Xu, Wei; Chen, Rong; Wan, Xuemei; Zhang, Haoluo; Wang, Liang; Wang, Xiaojie; Jiang, Linhong; Liu, Bin; Zhao, Ying; Chen, Yuanyuan; Dai, Yanping; Li, Min; Zhang, Huaqin; Bai, Lin; Zhang, Jie; Wang, Hongbo; Tian, Jingwei; Zhao, Yinglan; Cen, Xiaobo

doi:10.1038/s41401-021-00760-y

Cited by 5 publications

(3 citation statements)

References 45 publications

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“…Cocaine challenge following sensitization likewise increases extracellular glutamate in the dStr and NAc [12][13][14], which includes enhanced glutamatergic input from the PFC [15]. The molecular mechanisms underlying this enhancement of neurotransmission remain incompletely understood, although numerous cellular adaptations contributing to the expression of behavioral sensitization have been identified [16,17]. For example, mammalian/mechanistic target of rapamycin (mTOR) signaling is required for the expression of cocaine-induced locomotor sensitization through a mechanism that involves the trafficking of GluA2 AMPA receptors in the NAc [16].…”

Section: Introductionmentioning

confidence: 99%

“…The molecular mechanisms underlying this enhancement of neurotransmission remain incompletely understood, although numerous cellular adaptations contributing to the expression of behavioral sensitization have been identified [16,17]. For example, mammalian/mechanistic target of rapamycin (mTOR) signaling is required for the expression of cocaine-induced locomotor sensitization through a mechanism that involves the trafficking of GluA2 AMPA receptors in the NAc [16]. mTOR is a tyrosine protein kinase that regulates neurodevelopment, synaptic plasticity, and memory [18].…”

Section: Introductionmentioning

confidence: 99%

“…This study aimed to determine the impact of cocaine sensitization on total and pAMPK protein levels in synaptosomal and cytosolic protein fractions of the mPFC, dStr, and NAc of rats. We examined AMPK levels in separate functional subcellular domains, given that cocaine sensitization is known to impact the trafficking of other proteins involved in sensitization, including AMPARs [16]; furthermore, AMPK activation can increase AMPAR expression [40]. Most importantly, the kinase activity of AMPK in cortical tissue is enriched in both the nuclear and synaptosomal fractions compared to some kinases that show preferential activity in one or the other domain [41].…”

Section: Introductionmentioning

confidence: 99%

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Metformin Prevents Cocaine Sensitization: Involvement of Adenosine Monophosphate-Activated Protein Kinase Trafficking between Subcellular Compartments in the Corticostriatal Reward Circuit

Aruldas,

Orenstein,

Spencer

2023

IJMS

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Repeated cocaine exposure produces an enhanced locomotor response (sensitization) paralleled by biological adaptations in the brain. Previous studies demonstrated region-specific responsivity of adenosine monophosphate-activated protein kinase (AMPK) to repeated cocaine exposure. AMPK maintains cellular energy homeostasis at the organismal and cellular levels. Here, our objective was to quantify changes in phosphorylated (active) and total AMPK in the cytosol and synaptosome of the medial prefrontal cortex, nucleus accumbens, and dorsal striatum following acute or sensitizing cocaine injections. Brain region and cellular compartment selective changes in AMPK and pAMPK were found with some differences associated with acute withdrawal versus ongoing cocaine treatment. Our additional goal was to determine the behavioral and molecular effects of pretreatment with the indirect AMPK activator metformin. Metformin potentiated the locomotor activating effects of acute cocaine but blocked the development of sensitization. Sex differences largely obscured any protein-level treatment group effects, although pAMPK in the NAc shell cytosol was surprisingly reduced by metformin in rats receiving repeated cocaine. The rationale for these studies was to inform our understanding of AMPK activation dynamics in subcellular compartments and provide additional support for repurposing metformin for treating cocaine use disorder.

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