Altered dopamine release and uptake kinetics in mice lacking D2 receptors.
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.
Schmitz
Yvonne
Y
Department of Neurology, Columbia University, New York, New York 10032, USA.
Schmauss
Claudia
C
Sulzer
David
D
D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis / Q000378:metabolism; D000818:Animals; D017660:Autoreceptors / Q000378:metabolism*; D002540:Cerebral Cortex / Q000737:chemistry / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000737:chemistry / Q000378:metabolism; D004298:Dopamine / Q000032:analysis / Q000378:metabolism* / Q000493:pharmacokinetics*; D004558:Electric Stimulation; D018755:GABA Agonists / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D006719:Homovanillic Acid / Q000032:analysis / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D017729:Presynaptic Terminals / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000172:deficiency* / Q000378:metabolism*
D017660:Autoreceptors; D018755:GABA Agonists; D011956:Receptors, Cell Surface; D017448:Receptors, Dopamine D2; D015102:3,4-Dihydroxyphenylacetic Acid; D019204:GTP-Binding Proteins; D004298:Dopamine; D006719:Homovanillic Acid