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. Mathur, Meaghan Creed, David M. Dietz, Mary Kay Lobo
Neuron. 2017-12-01; 96(6): 1327-1341.e6
DOI: 10.1016/j.neuron.2017.11.037

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Chandra R(1), Engeln M(1), Schiefer C(1), Patton MH(2), Martin JA(3), Werner CT(3), Riggs LM(1), Francis TC(1), McGlincy M(1), Evans B(1), Nam H(1), Das S(1), Girven K(1), Konkalmatt P(4), Gancarz AM(3), Golden SA(5), Iñiguez SD(6), Russo SJ(5), Turecki G(7), Mathur BN(2), Creed M(2), Dietz DM(3), Lobo MK(8).

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: .

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.