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.
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Acknowledgements
We thank Dr Beverly Koller for providing NR1 KD mutant mice. We also thank Julie Harris, Wendy Roberts, and Katherine Clark for excellent technical assistance and Dr Jean Martin Beaulieu for helpful comments. This work was supported in part by a grant from NIH NS19576 (to MGC), NIDA DA02749 (to LAD) and NIDA DA017703 (to AJR). AL was supported in part by Academy of Finland. MC and AS were holders of Fonds de Recherche en Sante du Quebec fellowship, and AS is supported by CIHR.
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MGC receives compensation as a member of the Scientific Advisory Board of Acadia Pharmaceutical and owns stock in the company. He has consulted for Lundbeck and has received compensation. He has also received compensation in the form of honoraria for lecturing at various scientific meetings and academic institutions. None of the above presents any conflicts of interest with the results being described in the present paper.
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Ramsey, A., Laakso, A., Cyr, M. et al. Genetic NMDA Receptor Deficiency Disrupts Acute and Chronic Effects of Cocaine but not Amphetamine. Neuropsychopharmacol 33, 2701–2714 (2008). https://doi.org/10.1038/sj.npp.1301663
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DOI: https://doi.org/10.1038/sj.npp.1301663
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