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.
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Acknowledgements
We thank Dr William Carlezon and Dr Ole Isacson for the generous use of their equipment and software. We also thank Dr William Carlezon, Dr Glenn Konopaske, Dr Darrick Balu, and Dr Mark Thomas for their helpful discussions, as well as Jiamin Feng for the genotyping and maintenance of our mouse colony. This work was supported by an Andrew P. Merrill Research Fellowship granted to MAB, and National Institutes of Health grants R01MH05190 and P50MH0G0450 to JTC.
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Dr Joseph T. Coyle has received consulting fees from Abbott Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly, Puretech Ventures, and EnVivo Pharmaceuticals. He holds a patent on the use of D-serine for the treatment of serious mental illness; the patent is owned by the Massachusetts General Hospital but could yield royalties if developed. Dr Michael Benneyworth declares no conflict of interest.
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Benneyworth, M., Coyle, J. Altered Acquisition and Extinction of Amphetamine-Paired Context Conditioning in Genetic Mouse Models of Altered NMDA Receptor Function. Neuropsychopharmacol 37, 2496–2504 (2012). https://doi.org/10.1038/npp.2012.108
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DOI: https://doi.org/10.1038/npp.2012.108
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