Balanced NMDA receptor activity in dopamine D1 receptor (D1R)- And D2R-expressing medium spiny neurons is required for amphetamine sensitization

Lisa R Beutler, Matthew J. Wanat, Albert Quintana, Elisenda Sanz, Nigel S. Bamford, Larry S. Zweifel, Richard D. Palmiter

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

Signaling through N-methyl-D-aspartate-type glutamate receptors (NMDARs) is essential for the development of behavioral sensitization to psychostimulants such as amphetamine (AMPH). However, the cell type and brain region in which NMDAR signaling is required for AMPH sensitization remain unresolved. Here we use selective inactivation of Grin1, the gene encoding the essential NR1 subunit of NMDARs, in dopamine neurons or their medium spiny neuron (MSN) targets, to address this issue. We show that NMDAR signaling in dopamine neurons is not required for behavioral sensitization to AMPH. Conversely, removing NMDARs from MSNs that express the dopamine D1 receptor (D1R) significantly attenuated AMPH sensitization, and conditional, virus-mediated restoration of NR1 in D1R neurons in the nucleus accumbens (NAc) of these animals rescued sensitization. Interestingly, sensitization could also be restored by virus-mediated inactivation of NR1 in all remaining neurons in the NAc of animals lacking NMDARs on D1R neurons, or by removing NMDARs from all MSNs. Taken together, these data indicate that unbalanced loss of NMDAR signaling in D1RMSNs alone prevents AMPH sensitization, whereas a balanced loss of NMDARs from both D1R and dopamine D2 receptor-expressing (D2R) MSNs is permissive for sensitization.

Original languageEnglish (US)
Pages (from-to)4206-4211
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number10
DOIs
StatePublished - Mar 8 2011

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Balanced NMDA receptor activity in dopamine D1 receptor (D1R)- And D2R-expressing medium spiny neurons is required for amphetamine sensitization'. Together they form a unique fingerprint.

Cite this