Cell-Type Specific Insertion of GluA2-Lacking AMPARs with Cocaine Exposure Leading to Sensitization, Cue-Induced Seeking, and Incubation of Craving

Neuropsychopharmacology. 2016 Jun;41(7):1779-89. doi: 10.1038/npp.2015.345. Epub 2015 Nov 20.


Addiction is a behavioral disease, of which core components can be modeled in rodents. Much evidence implicates drug-evoked synaptic plasticity in cocaine-evoked locomotor sensitization, cue-induced cocaine seeking, and incubation of cocaine craving. However, the type of plasticity evoked by different modalities of cocaine administration (eg contingent vs non-contingent) and its role in reshaping circuit function remains largely elusive. Here we exposed mice to various regimens of cocaine and recorded excitatory transmission onto identified medium-sized spiny neurons (MSN, expressing fluorescent proteins under the control of either D1R or D2R dopamine receptor promotor) in the nucleus accumbens at time points when behavioral adaptations are observed. In D1-MSN, we found the presence of GluA2-lacking α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) after single or chronic non-contingent exposure to cocaine as well as after cocaine self-administration (SA). We also report an increase in the AMPA/NMDA ratio (A/N) in D1-MSN, which was observed only after repeated passive injections associated with locomotor sensitization as well as in a condition of SA leading to seeking behavior. Remarkably, insertion of GluA2-lacking AMPARs was also detected in D2-MSN after SA of a high dose of cocaine but not regular dose (1.5 vs 0.75 mg/kg), which was the only condition where incubation of cocaine craving was observed in this study. Moreover, synapses containing GluA2-lacking AMPARs belonged to amygdala inputs in D2-MSN and to medial prefrontal cortex inputs in D1-MSN. Taken together this study allows for a refinement of a circuit model of addiction based on specific synaptic changes induced by cocaine.

MeSH terms

  • 2-Amino-5-phosphonovalerate / pharmacology
  • Animals
  • Brain / cytology
  • Cocaine / administration & dosage*
  • Cocaine-Related Disorders / physiopathology*
  • Conditioning, Operant / drug effects
  • Cues*
  • Drug-Seeking Behavior / drug effects*
  • Excitatory Amino Acid Antagonists / pharmacology
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Locomotion / drug effects
  • Locomotion / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neuronal Plasticity / drug effects
  • Neurons / drug effects
  • Receptors, AMPA / deficiency*
  • Receptors, AMPA / genetics
  • Receptors, Dopamine / deficiency
  • Receptors, Dopamine / genetics
  • Transduction, Genetic
  • Vasoconstrictor Agents / administration & dosage*


  • Excitatory Amino Acid Antagonists
  • Receptors, AMPA
  • Receptors, Dopamine
  • Vasoconstrictor Agents
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • 2-Amino-5-phosphonovalerate
  • Cocaine
  • glutamate receptor ionotropic, AMPA 2