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

Michael A Benneyworth, Joseph T. Coyle

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2496-2504
Number of pages9
JournalNeuropsychopharmacology
Volume37
Issue number11
DOIs
StatePublished - Oct 1 2012

Fingerprint

Genetic Models
Amphetamine
N-Methyl-D-Aspartate Receptors
Nucleus Accumbens
Glycine Plasma Membrane Transport Proteins
Aptitude
Glutamate Receptors
Pharmaceutical Preparations
Glycine
Serine
Substance-Related Disorders
Cues
Psychological Extinction
Conditioning (Psychology)
Comorbidity
Schizophrenia
Spine
Learning

Keywords

  • D-serine
  • NMDA receptor
  • addiction
  • behavioral sensitization
  • extinction
  • glycine

Cite this

Altered acquisition and extinction of amphetamine-paired context conditioning in genetic mouse models of altered nmda receptor function. / Benneyworth, Michael A; Coyle, Joseph T.

In: Neuropsychopharmacology, Vol. 37, No. 11, 01.10.2012, p. 2496-2504.

Research output: Contribution to journalArticle

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