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PNAS 98 (20): 11047-11054

Copyright © 2001 by the National Academy of Sciences.

Colloquium Paper


Glutamatergic modulation of hyperactivity in mice lacking the dopamine transporter

Raul R. Gainetdinov, Amy R. Mohn, Laura M. Bohn, and Marc G. Caron*

Howard Hughes Medical Institute Laboratories, Departments of Cell Biology and Medicine, Duke University Medical Center, Durham, NC 27710

Abstract: In the brain, dopamine exerts an important modulatory influence over behaviors such as emotion, cognition, and affect as well as mechanisms of reward and the control of locomotion. The dopamine transporter (DAT), which reuptakes the released neurotransmitter into presynaptic terminals, is a major determinant of the intensity and duration of the dopaminergic signal. Knockout mice lacking the dopamine transporter (DAT-KO mice) display marked changes in dopamine homeostasis that result in elevated dopaminergic tone and pronounced locomotor hyperactivity. A feature of DAT-KO mice is that their hyperactivity can be inhibited by psychostimulants and serotonergic drugs. The pharmacological effect of these drugs occurs without any observable changes in dopaminergic parameters, suggesting that other neurotransmitter systems in addition to dopamine might contribute to the control of locomotion in these mice. We report here that the hyperactivity of DAT-KO mice can be markedly further enhanced when N-methyl-D-aspartate receptor-mediated glutamatergic transmission is blocked. Conversely, drugs that enhance glutamatergic transmission, such as positive modulators of L-α-amino-3-hydroxy-5-methylisoxazole-4-propionate glutamate receptors, suppress the hyperactivity of DAT-KO mice. Interestingly, blockade of N- methyl-D-aspartate receptors prevented the inhibitory effects of both psychostimulant and serotonergic drugs on hyperactivity. These findings support the concept of a reciprocal functional interaction between dopamine and glutamate in the basal ganglia and suggest that agents modulating glutamatergic transmission may represent an approach to manage conditions associated with dopaminergic dysfunction.

* To whom reprint requests should be addressed. E-mail: caron002{at}

This paper was presented at the Inaugural Arthur M. Sackler Colloquium of the National Academy of Sciences, "Neural Signaling," held February 15–17, 2001, at the National Academy of Sciences in Washington, DC.

{dagger} Cooper, D. C., Hu, X.-T., Jones, S. R., Giros, B., Caron, M. G. & White, F. J. (1997) Soc. Neurosci. Abstr. 23, 1210.

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