Stress and Cocaine Trigger Divergent and Cell Type-Specific Regulation of Synaptic Transmission at Single Spines in Nucleus Accumbens

Biol Psychiatry. 2016 Jun 1;79(11):898-905. doi: 10.1016/j.biopsych.2015.05.022. Epub 2015 Jun 6.


Background: Repeated exposure to cocaine or social stress leads to lasting structural and functional synaptic alterations in medium spiny neurons (MSNs) of nucleus accumbens (NAc). Although cocaine-induced and stress-induced structural changes in dendritic spines have been well documented, few studies have investigated functional consequences of cocaine and stress at the level of single spines.

Methods: We exposed mice to chronic cocaine or chronic social defeat stress and used two-photon laser scanning microscopy with glutamate photo-uncaging and whole-cell recording to examine synaptic strength at individual spines on two distinct types of NAc MSNs in acute slices after 24 hours of cocaine withdrawal and after chronic social defeat stress.

Results: In animals treated with cocaine, average synaptic strength was reduced specifically at large mushroom spines of MSNs expressing dopamine receptor type 1 (D1-MSNs). In contrast, cocaine promoted a rightward shift in the distribution of synaptic weights toward larger synaptic responses in MSNs expressing dopamine receptor type 2 (D2-MSNs). After chronic social defeat stress, resilient animals displayed an upregulation of synaptic strength at large mushroom spines of D1-MSNs and a concomitant downregulation in D2-MSNs. Although susceptible mice did not exhibit a significant overall change in synaptic strength on D1-MSNs or D2-MSNs, we observed a slight leftward shift in cumulative distribution of large synaptic responses in both cell types.

Conclusions: This study provides the first functional cell type-specific and spine type-specific comparison of synaptic strength at a single spine level between cocaine-induced and stress-induced neuroadaptations and demonstrates that psychoactive drugs and stress trigger divergent changes in synaptic function in NAc.

Keywords: Chronic social defeat stress; Cocaine addiction; Dendritic spine; Glutamate uncaging; Nucleus accumbens; Synaptic transmission.

MeSH terms

  • Animals
  • Cocaine / pharmacology*
  • Dendritic Spines / drug effects
  • Dendritic Spines / physiology
  • Dominance-Subordination
  • Dopamine Uptake Inhibitors / pharmacology*
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • Glutamic Acid / metabolism
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microscopy, Confocal
  • Nucleus Accumbens / drug effects*
  • Nucleus Accumbens / physiopathology*
  • Patch-Clamp Techniques
  • Receptors, Dopamine D1 / metabolism
  • Receptors, Dopamine D2 / genetics
  • Receptors, Dopamine D2 / metabolism
  • Stress, Psychological / physiopathology*
  • Substance Withdrawal Syndrome / physiopathology
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology
  • Tissue Culture Techniques


  • DRD2 protein, mouse
  • Dopamine Uptake Inhibitors
  • Drd1 protein, mouse
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • Glutamic Acid
  • Cocaine