Drp1 Mitochondrial Fission in D1 Neurons Mediates Behavioral and Cellular Plasticity during Early Cocaine Abstinence

Ramesh Chandra, Michel Engeln, Christopher Schiefer, Mary H. Patton, Jennifer A. Martin, Craig T. Werner, Lace M. Riggs, T. Chase Francis, Madeleine McGlincy, Brianna Evans, Hyungwoo Nam, Shweta Das, Kasey Girven, Prasad Konkalmatt, Amy M. Gancarz, Sam A. Golden, Sergio D. Iñiguez, Scott J. Russo, Gustavo Turecki, Brian N. MathurMeaghan Creed, David M. Dietz, Mary Kay Lobo

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

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. Chandra, Engeln et al. show that mitochondrial division and its molecular mediator, Drp1, are increased in nucleus accumbens D1-MSNs after repeated cocaine. Pharmacological or genetic blockade of mitochondrial division prevents physiological and behavioral outcomes to cocaine during early drug abstinence.

Original languageEnglish
Pages (from-to)1327-1341.e6
JournalNeuron
Volume96
Issue number6
DOIs
StatePublished - Dec 20 2017
Externally publishedYes

Keywords

  • Drp1
  • cocaine
  • medium spiny neurons
  • mitochondria
  • nucleus accumbens
  • self-administration

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    Chandra, R., Engeln, M., Schiefer, C., Patton, M. H., Martin, J. A., Werner, C. T., Riggs, L. M., Francis, T. C., McGlincy, M., Evans, B., Nam, H., Das, S., Girven, K., Konkalmatt, P., Gancarz, A. M., Golden, S. A., Iñiguez, S. D., Russo, S. J., Turecki, G., ... Lobo, M. K. (2017). Drp1 Mitochondrial Fission in D1 Neurons Mediates Behavioral and Cellular Plasticity during Early Cocaine Abstinence. Neuron, 96(6), 1327-1341.e6. https://doi.org/10.1016/j.neuron.2017.11.037