Altered acquisition and extinction of amphetamine-paired context conditioning in genetic mouse models of altered NMDA receptor function

Neuropsychopharmacology. 2012 Oct;37(11):2496-504. doi: 10.1038/npp.2012.108. Epub 2012 Jul 4.


Repeated intermittent exposure to amphetamine (AMPH) results in the development of persistent behavioral and neurological changes. When drug exposure is paired with a specific environment, contextual cues can control conditioned responses, context-specific sensitization, and alterations in dendritic morphology in the nucleus accumbens (NAc). Intact N-methyl-D-aspartate (NMDA) glutamate receptor signaling is thought to be required for associative learning. The acquisition of context-specific behavioral sensitization to AMPH and extinction of conditioned hyperactivity have been investigated in two genetically modified mouse strains: the serine racemase homozygous knockout (SR-/-) and glycine transporter 1 heterozygous mutant (GlyT1-/+). These strains have reciprocally altered NMDA receptor co-agonists, D-serine and glycine, levels that result in decreased (SR-/-) or increased (GlyT1-/+) NMDA receptor signaling. AMPH-induced changes in dendritic morphology in the NAc were also examined. SR-/- mice showed reduced expression of context-specific sensitization and conditioned hyperactivity. However, the conditioned hyperactivity in these mice is completely resistant to extinction. Extinction reversed AMPH-induced increased in NAc spine density in wild-type but not SR-/- mice. GlyT1 -/+ mice showed a more rapid acquisition of sensitization, but no alteration in the extinction of conditioned hyperactivity. The SR-/- data demonstrate that a genetic model of NMDA receptor hypofunction displays a reduced ability to extinguish conditioned responses to drug-associated stimuli. Findings also demonstrate that the morphological changes in the NAc encode conditioned responses that are sensitive to extinction and reduced NMDA receptor activity. NMDA receptor hypofunction may contribute to the comorbidity of substance abuse in schizophrenia.

Publication types

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

MeSH terms

  • Amphetamine / administration & dosage*
  • Analysis of Variance
  • Animals
  • Behavioral Symptoms / chemically induced
  • Behavioral Symptoms / genetics
  • Behavioral Symptoms / physiopathology
  • Central Nervous System Stimulants / administration & dosage*
  • Conditioning, Psychological / drug effects*
  • Cues
  • Dendritic Spines / drug effects
  • Dendritic Spines / genetics
  • Dendritic Spines / ultrastructure
  • Dose-Response Relationship, Drug
  • Extinction, Psychological / drug effects*
  • Glycine Plasma Membrane Transport Proteins / genetics
  • Hyperkinesis / chemically induced
  • Hyperkinesis / genetics
  • Hyperkinesis / physiopathology
  • L-Serine Dehydratase / deficiency
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Motor Activity / drug effects
  • Motor Activity / genetics
  • Mutation / genetics*
  • Neurons / drug effects
  • Neurons / ultrastructure
  • Nucleus Accumbens / cytology
  • Nucleus Accumbens / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Silver Staining
  • Time Factors


  • Central Nervous System Stimulants
  • Glycine Plasma Membrane Transport Proteins
  • Receptors, N-Methyl-D-Aspartate
  • Slc6a9 protein, mouse
  • Amphetamine
  • L-Serine Dehydratase