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- Title
Cascades of Homeostatic Dysregulation Promote Incubation of Cocaine Craving.
- Authors
Junshi Wang; Masago Ishikawa; Yue Yang; Mami Otaka; Kim, James Y.; Gardner, George R.; Stefanik, Michael T.; Milovanovic, Mike; Huang, Yanhua H.; Hell, Johannes W.; Wolf, Marina E.; Schlüter, Oliver M.; Yan Dong
- 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.
- Subjects
COCAINE; NUCLEUS accumbens; DRUG addiction; DRUG withdrawal symptoms; DRUG administration
- Publication
Journal of Neuroscience, 2018, Vol 38, Issue 18, p4316
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.3291-17.2018