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Neuron. 2008 Aug 14;59(3):486-96. doi: 10.1016/j.neuron.2008.05.028.

Role of NMDA receptors in dopamine neurons for plasticity and addictive behaviors.

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1
Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. larryz@u.washington.edu

Abstract

A single exposure to drugs of abuse produces an NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) of AMPA receptor (AMPAR) currents in DA neurons; however, the importance of LTP for various aspects of drug addiction is unclear. To test the role of NMDAR-dependent plasticity in addictive behavior, we genetically inactivated functional NMDAR signaling exclusively in DA neurons (KO mice). Inactivation of NMDARs results in increased AMPAR-mediated transmission that is indistinguishable from the increases associated with a single cocaine exposure, yet locomotor responses to multiple drugs of abuse were unaltered in the KO mice. The initial phase of locomotor sensitization to cocaine is intact; however, the delayed sensitization that occurs with prolonged cocaine withdrawal did not occur. Conditioned behavioral responses for cocaine-testing environment were also absent in the KO mice. These findings provide evidence for a role of NMDAR signaling in DA neurons for specific behavioral modifications associated with drug seeking behaviors.

PMID:
18701073
PMCID:
PMC2556153
DOI:
10.1016/j.neuron.2008.05.028
[Indexed for MEDLINE]
Free PMC Article

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