Glutamatergic modulation of hyperactivity in mice lacking the dopamine transporter

In the brain, dopamine exerts an important modulatory influence over behavi ors such as emotion, cognition, and affect as well as mechanisms of reward and the control of locomotion. The dopamine transporter (DAT), which reupta kes the released neurotransmitter into presynaptic terminals, is a major de terminant of the intensity and duration of the dopaminergic signal. Knockou t mice lacking the dopamine transporter (DAT-KO mice) display marked change s in dopamine homeostasis that result in elevated dopaminergic tone and pro nounced locomotor hyperactivity. A feature of DAT-KO mice is that their hyp eractivity can be inhibited by psychostimulants and serotonergic drugs. The pharmacological effect of these drugs occurs without any observable change s in dopaminergic parameters, suggesting that other neurotransmitter system s 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 mar kedly further enhanced when N-methyl-D-aspartate receptor-mediated glutamat ergic transmission is blocked. Conversely, drugs that enhance glutamatergic transmission, such as positive modulators of L-alpha -amino-3-hydroxy-5-me thylisoxazole-4-propionate glutamate receptors, suppress the hyperactivity of DAT-KO mice. Interestingly, blockade of Nmethyl-D-aspartate receptors pr evented the inhibitory effects of both psychostimulant and serotonergic dru gs on hyperactivity. These findings support the concept of a reciprocal fun ctional 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.