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The Journal of Neuroscience, September 15, 2002, 22(18):8002-8009

Altered Dopamine Release and Uptake Kinetics in Mice Lacking D₂ Receptors

Yvonne Schmitz¹, Claudia Schmauss^{2, 3}, and David Sulzer^{1, 2, 3}

Departments of ¹ Neurology and ² Psychiatry, Columbia University, and ³ Department of Neuroscience, New York Psychiatric Institute, New York, New York 10032

Dysregulation of dopamine transmission is thought to contribute to schizophrenic psychosis and drug dependence. Dopamine release is regulated by D₂ dopamine autoreceptors, and D₂ receptor ligands are used to treat psychosis and addiction. To elucidate the long-term effects of D₂ autoreceptor activity on dopamine signaling, dopamine overflow evoked by single or paired-pulse stimulation was compared in striatal slices from D₂-null mutant and wild-type mice. Quinpirole, a D₂/D₃ receptor agonist, had no effect on evoked dopamine release in D₂ mutant mice, indicating that D₂ receptors are the only release-regulating receptors at the axon terminal. Dopamine release inhibition by GABA_B receptor activation was unchanged in D₂ mutant mice, suggesting that other G-protein-coupled pathways remained normal in the absence of D₂ autoreceptors. Paired-pulse stimulation revealed that autoinhibition of dopamine release was maximal 500 msec after stimulation and lasted <5 sec. In D₂-null mutants, dopamine overflow in response to single stimuli was severely decreased. Experiments with the uptake inhibitor nomifensine indicated that this was caused by enhanced dopamine uptake rather than reduced release. Analysis of dopamine overflow kinetics using a simulation model suggested that the enhanced uptake was caused by an increase in the maximal velocity of uptake, V_max. These results from D₂-null mutant mice support the suggestion that D₂ autoreceptors and dopamine transporters interact to regulate the amplitude and timing of dopamine signals.

Key words: dopamine; D₂ receptor; autoreceptor; dopamine transporter; release; paired-pulse depression; striatum

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22188002-08$05.00/0

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