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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cocaine / administration & dosage
  • Cocaine / pharmacology*
  • Conditioning, Operant / drug effects
  • Conditioning, Operant / physiology
  • Dopamine Uptake Inhibitors / administration & dosage
  • Dopamine Uptake Inhibitors / pharmacology
  • Dopaminergic Neurons / drug effects*
  • Dopaminergic Neurons / ultrastructure
  • Dynamins / genetics
  • Dynamins / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Locomotion / drug effects*
  • Locomotion / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / genetics
  • Nucleus Accumbens / cytology
  • Quinazolinones / pharmacology
  • Receptors, Dopamine D1 / genetics
  • Receptors, Dopamine D1 / metabolism*
  • Receptors, Dopamine D2 / genetics
  • Receptors, Dopamine D2 / metabolism
  • Self Administration

Substances

  • 3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone
  • Dopamine Uptake Inhibitors
  • Enzyme Inhibitors
  • Quinazolinones
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • Dnm1l protein, mouse
  • Dynamins
  • Cocaine