Rapid Synaptogenesis in the Nucleus Accumbens Is Induced by a Single Cocaine Administration and Stabilized by Mitogen-Activated Protein Kinase Interacting Kinase-1 Activity

Biol Psychiatry. 2017 Dec 1;82(11):806-818. doi: 10.1016/j.biopsych.2017.03.014. Epub 2017 Mar 29.


Background: Repeated cocaine exposure produces new spine formation in striatal projection neurons (SPNs) of the nucleus accumbens. However, an acute exposure to cocaine can trigger long-lasting synaptic plasticity in SPNs leading to behavioral alterations. This raises the intriguing question as to whether a single administration of cocaine could enduringly modify striatal connectivity.

Methods: A three-dimensional morphometric analysis of presynaptic glutamatergic boutons and dendritic spines was performed on SPNs 1 hour and 1 week after a single cocaine administration. Time-lapse two-photon microscopy in adult slices was used to determine the precise molecular-events sequence responsible for the rapid spine formation.

Results: A single injection triggered a rapid synaptogenesis and persistent increase in glutamatergic connectivity in SPNs from the shell part of the nucleus accumbens, specifically. Synapse formation occurred through clustered growth of active spines contacting pre-existing axonal boutons. Spine growth required extracellular signal-regulated kinase activation, while spine stabilization involved transcription-independent protein synthesis driven by mitogen-activated protein kinase interacting kinase-1, downstream from extracellular signal-regulated kinase. The maintenance of new spines driven by mitogen-activated protein kinase interacting kinase-1 was essential for long-term connectivity changes induced by cocaine in vivo.

Conclusions: Our study originally demonstrates that a single administration of cocaine is able to induce stable synaptic rewiring in the nucleus accumbens, which will likely influence responses to subsequent drug exposure. It also unravels a new functional role for cocaine-induced extracellular signal-regulated kinase pathway independently of nuclear targets. Finally, it reveals that mitogen-activated protein kinase interacting kinase-1 has a pivotal role in cocaine-induced connectivity.

Keywords: Cocaine; Dendritic spine; Extracellular signal-regulated kinase; MAP kinase interacting kinase; Striatum; Synaptogenesis.

MeSH terms

  • Animals
  • Cocaine / pharmacology*
  • Dendritic Spines / drug effects
  • Dopamine Uptake Inhibitors / pharmacology*
  • Enzyme Inhibitors / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression Regulation / drug effects*
  • Gene Expression Regulation / genetics
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • MAP Kinase Kinase 1 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neostriatum / metabolism
  • Neurogenesis / drug effects*
  • Nucleus Accumbens / cytology
  • Nucleus Accumbens / drug effects*
  • Proto-Oncogene Proteins c-fos / metabolism
  • Receptors, Dopamine D1 / metabolism
  • Sirolimus / pharmacology
  • Synapses / drug effects
  • Synapses / physiology*
  • Vesicular Glutamate Transport Protein 1 / genetics
  • Vesicular Glutamate Transport Protein 1 / metabolism


  • Dopamine Uptake Inhibitors
  • Enzyme Inhibitors
  • Luminescent Proteins
  • Proto-Oncogene Proteins c-fos
  • Receptors, Dopamine D1
  • Vesicular Glutamate Transport Protein 1
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase 1
  • Cocaine
  • Sirolimus