ALTERATIONS IN DOPAMINE RELEASE BUT NOT DOPAMINE AUTORECEPTOR FUNCTION IN DOPAMINE D-3 RECEPTOR MUTANT MICE

Dopamine (DA) autoreceptors expressed along the somatodendritic extent of midbrain DA neurons modulate impulse activity, whereas those expre ssed at DA nerve terminals regulate both DA synthesis and release. Con siderable evidence has indicated that these DA autoreceptors are of th e D-2 subtype of DA receptors. However, many pharmacological studies h ave suggested an autoreceptor role for the DA D-3 receptor. This possi bility was tested with mice lacking the D-3 receptor as a result of ge ne targeting. The basal firing rates of DA neurons within both the sub stantia nigra and ventral tegmental area were not different in D-3 rec eptor mutant and wild-type mice. The putative D-3 receptor-selective a gonist 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 midbr ain DA neurons in the two groups of mice. In the gamma-butyrolactone ( GEL) model of DA autoreceptor function, mutant and wild-type mice were identical with respect to striatal DA synthesis and its suppression b y PD 128907. In vivo microdialysis studies of DA release in ventral st rictum revealed higher basal levels of extracellular DA in mutant mice but similar inhibitory effects of PD 128907 in mutant and wildtype mi ce. These results suggest that the effects of PD 128907 on dopamine ce ll function reflect stimulation of D-2 as opposed to D-3 receptors. Al though D-3 receptors do not seem to be significantly involved in DA au toreceptor function, they may participate in postsynaptically activate d short-loop feedback modulation of DA release.