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Neuron. 2017 Dec 20;96(6):1327-1341.e6. doi: 10.1016/j.neuron.2017.11.037.

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

Author information

1
Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA.
2
Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA.
3
Department of Pharmacology and Toxicology, The Research Institution on Addictions, State University of New York at Buffalo, Buffalo, NY, USA.
4
Division of Renal Diseases and Hypertension, The George Washington University, Washington, D.C., USA.
5
Fishberg Department of Neuroscience and Friedman Brain Institute, Graduate School of Biomedical Sciences at the Icahn School of Medicine at Mount Sinai, New York, NY, USA.
6
Department of Psychology, University of Texas at El Paso, El Paso, TX, USA.
7
McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montréal, QC, Canada.
8
Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address: mklobo@som.umaryland.edu.

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.

KEYWORDS:

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

PMID:
29268097
PMCID:
PMC5747376
DOI:
10.1016/j.neuron.2017.11.037
[Indexed for MEDLINE]
Free PMC Article

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