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The Journal of Neuroscience, March 15, 1998, 18(6):2231-2238
Alterations in Dopamine Release But Not Dopamine Autoreceptor
Function in Dopamine D3 Receptor Mutant Mice
Timothy E.
Koeltzow1,
Ming
Xu2,
Donald C.
Cooper1,
Xiu-Ti
Hu1,
Susumu
Tonegawa2,
Marina E.
Wolf1, and
Francis J.
White1
1 Department of Neuroscience, Finch University of
Health Sciences, Chicago Medical School, North Chicago, Illinois
60064-3095, and 2 Howard Hughes Medical Institute, Center
for Learning and Memory, Center for Cancer Research, and Department of
Biology, Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139
Dopamine (DA) autoreceptors expressed along the somatodendritic
extent of midbrain DA neurons modulate impulse activity, whereas those
expressed at DA nerve terminals regulate both DA synthesis and release.
Considerable evidence has indicated that these DA autoreceptors are of
the D2 subtype of DA receptors. However, many
pharmacological studies have suggested an autoreceptor role for the DA
D3 receptor. This possibility was tested with mice lacking
the D3 receptor as a result of gene targeting. The basal firing rates of DA neurons within both the substantia nigra and ventral
tegmental area were not different in D3 receptor
mutant and wild-type mice. The putative D3
receptor-selective agonist R(+)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-(1)benzopyrano(4,3-b) 1,4-oxazin-9-ol (PD 128907) was equipotent at inhibiting the activity of both populations of midbrain DA neurons in the two groups of mice. In the
 -butyrolactone (GBL) model of DA autoreceptor function, mutant and
wild-type mice were identical with respect to striatal DA synthesis and
its suppression by PD 128907. In vivo microdialysis studies of DA release in ventral striatum revealed higher basal levels
of extracellular DA in mutant mice but similar inhibitory effects of PD
128907 in mutant and wild-type mice. These results suggest that the
effects of PD 128907 on dopamine cell function reflect stimulation of
D2 as opposed to D3 receptors. Although D3 receptors do not seem to be significantly involved in DA
autoreceptor function, they may participate in postsynaptically
activated short-loop feedback modulation of DA release.
Key words:
D3 receptors; mutant mice; dopamine
autoreceptors; dopamine receptors; dopamine neurons; dopamine release; dopamine synthesis
Copyright © 1998 Society for Neuroscience 0270-6474/98/1862231-08$05.00/0
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