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Cascades of Homeostatic Dysregulation Promote Incubation of Cocaine Craving.
Wang, Junshi; Ishikawa, Masago; Yang, Yue; Otaka, Mami; Kim, James Y; Gardner, George R; Stefanik, Michael T; Milovanovic, Mike; Huang, Yanhua H; Hell, Johannes W; Wolf, Marina E; Schlüter, Oliver M; Dong, Yan.
Affiliation
  • Wang J; Departments of Neuroscience.
  • Ishikawa M; Departments of Neuroscience.
  • Yang Y; Departments of Neuroscience.
  • Otaka M; Departments of Neuroscience.
  • Kim JY; Departments of Neuroscience.
  • Gardner GR; Departments of Neuroscience.
  • Stefanik MT; Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064, and.
  • Milovanovic M; Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064, and.
  • Huang YH; Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260.
  • Hell JW; Department of Pharmacology, University of California, Davis, Davis, California 95615.
  • Wolf ME; Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064, and.
  • Schlüter OM; Departments of Neuroscience.
  • Dong Y; Department of Psychiatry and Psychotherapy, University Medical Center, 37075 Göttingen, Germany.
J Neurosci ; 38(18): 4316-4328, 2018 05 02.
Article in En | MEDLINE | ID: mdl-29626166
ABSTRACT
In human drug users, cue-induced drug craving progressively intensifies after drug abstinence, promoting drug relapse. This time-dependent progression of drug craving is recapitulated in rodent models, in which rats exhibit progressive intensification of cue-induced drug seeking after withdrawal from drug self-administration, a phenomenon termed incubation of drug craving. Although recent results suggest that functional alterations of the nucleus accumbens (NAc) contribute to incubation of drug craving, it remains poorly understood how NAc function evolves after drug withdrawal to progressively intensify drug seeking. The functional output of NAc relies on how the membrane excitability of its principal medium spiny neurons (MSNs) translates excitatory synaptic inputs into action potential firing. Here, we report a synapse-membrane homeostatic crosstalk (SMHC) in male rats, through which an increase or decrease in the excitatory synaptic strength induces a homeostatic decrease or increase in the intrinsic membrane excitability of NAc MSNs, and vice versa. After short-term withdrawal from cocaine self-administration, despite no actual change in the AMPA receptor-mediated excitatory synaptic strength, GluN2B NMDA receptors, the SMHC sensors of synaptic strength, are upregulated. This may create false SMHC signals, leading to a decrease in the membrane excitability of NAc MSNs. The decreased membrane excitability subsequently induces another round of SMHC, leading to synaptic accumulation of calcium-permeable AMPA receptors and upregulation of excitatory synaptic strength after long-term withdrawal from cocaine. Disrupting SMHC-based dysregulation cascades after cocaine exposure prevents incubation of cocaine craving. Thus, cocaine triggers cascades of SMHC-based dysregulation in NAc MSNs, promoting incubated cocaine seeking after drug withdrawal.SIGNIFICANCE STATEMENT Here, we report a bidirectional homeostatic plasticity between the excitatory synaptic input and membrane excitability of nucleus accumbens (NAc) medium spiny neurons (MSNs), through which an increase or decrease in the excitatory synaptic strength induces a homeostatic decrease or increase in the membrane excitability, and vice versa. Cocaine self-administration creates a false homeostatic signal that engages this synapse-membrane homeostatic crosstalk mechanism, and produces cascades of alterations in excitatory synapses and membrane properties of NAc MSNs after withdrawal from cocaine. Experimentally preventing this homeostatic dysregulation cascade prevents the progressive intensification of cocaine seeking after drug withdrawal. These results provide a novel mechanism through which drug-induced homeostatic dysregulation cascades progressively alter the functional output of NAc MSNs and promote drug relapse.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Cocaine-Related Disorders / Craving / Homeostasis Limits: Animals Language: En Journal: J Neurosci Year: 2018 Document type: Article

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Cocaine-Related Disorders / Craving / Homeostasis Limits: Animals Language: En Journal: J Neurosci Year: 2018 Document type: Article