Neuron
Volume 96, Issue 6, 20 December 2017, Pages 1327-1341.e6
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Article
Drp1 Mitochondrial Fission in D1 Neurons Mediates Behavioral and Cellular Plasticity during Early Cocaine Abstinence

https://doi.org/10.1016/j.neuron.2017.11.037Get rights and content
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Highlights

  • Cocaine promotes mitochondrial fission in NAc D1-MSNs through Drp1 activation

  • Mdivi-1 blunts drug-induced behaviors and excitatory synaptic function in D1-MSNs

  • NAc D1-MSN genetic reduction of Drp1 blunts drug seeking after early abstinence

  • Enhancing fission in D1-MSNs potentiates drug seeking after long-term abstinence

Summary

Altered brain energy homeostasis is a key adaptation occurring in the cocaine-addicted brain, but the effect of cocaine on the fundamental source of energy, mitochondria, is unknown. We demonstrate an increase of dynamin-related protein-1 (Drp1), the mitochondrial fission mediator, in nucleus accumbens (NAc) after repeated cocaine exposure and in cocaine-dependent individuals. Mdivi-1, a demonstrated fission inhibitor, blunts cocaine seeking and locomotor sensitization, while blocking c-Fos induction and excitatory input onto dopamine receptor-1 (D1) containing NAc medium spiny neurons (MSNs). Drp1 and fission promoting Drp1 are increased in D1-MSNs, consistent with increased smaller mitochondria in D1-MSN dendrites after repeated cocaine. Knockdown of Drp1 in D1-MSNs blocks drug seeking after cocaine self-administration, while enhancing the fission promoting Drp1 enhances seeking after long-term abstinence from cocaine. We demonstrate a role for altered mitochondrial fission in the NAc, during early cocaine abstinence, suggesting potential therapeutic treatment of disrupting mitochondrial fission in cocaine addiction.

Keywords

medium spiny neurons
nucleus accumbens
self-administration
mitochondria
Drp1
cocaine

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These authors contributed equally

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