1. ¹Department of Cell Biology, Duke University Medical Center, Durham, NC, USA
2. ²Department of Psychology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Correspondence: Dr MG Caron, Department of Cell Biology, Duke University Medical Center, Box 3287, Room 481 CARL Building, Research Drive, Durham, NC 27710, USA. Tel: +1 919 684 5433; Fax: +1 919 681 8641; E-mail: caron002@mc.duke.edu

³Current address: Neuroscience Research Group, Universite du Quebec a Trois-Rivieres, CP500, Trois-Rivieres, QC, Canada G9A 5H7.

Received 13 July 2007; Revised 2 November 2007; Accepted 24 November 2007; Published online 9 January 2008.

Abstract

NMDA receptor-mediated glutamate transmission is required for several forms of neuronal plasticity. Its role in the neuronal responses to addictive drugs is an ongoing subject of investigation. We report here that the acute locomotor-stimulating effect of cocaine is absent in NMDA receptor-deficient mice (NR1-KD). In contrast, their acute responses to amphetamine and to direct dopamine receptor agonists are not significantly altered. The striking attenuation of cocaine's acute effects is not likely explained by alterations in the dopaminergic system of NR1-KD mice, since most parameters of pre- and postsynaptic dopamine function are unchanged. Consistent with the behavioral findings, cocaine induces less c-Fos expression in the striatum of these mice, while amphetamine-induced c-Fos expression is intact. Furthermore, chronic cocaine-induced sensitization and conditioned place preference are attenuated and develop more slowly in mutant animals, but amphetamine's effects are not altered significantly. Our results highlight the importance of NMDA receptor-mediated glutamatergic transmission specifically in cocaine actions, and support a hypothesis that cocaine and amphetamine elicit their effects through differential actions on signaling pathways.