Dopamine D2 receptor-deficient mice exhibit decreased dopamine transporter function but no changes in dopamine release in dorsal striatum

Presynaptic D-2 dopamine (DA) autoreceptors, which are well known to modulate DA release, have recently been shown to regulate DA transporter (DAT) activity, To examine the effects of D-2 DA receptor deficiency on DA release and DAT activity in dorsal striatum, we used mice genetically engineered to have two (D-2(+/+)), one (D-2(+/-)), or no (D-2(-/-)) functional copies of the gene coding for the D-2 DA receptor. In vivo microdialysis studies demonstrated that basal and Kf-evoked extracellular DA concentrations were similar in all three genotypes, However, using in vivo electrochemistry, the D-2(-/-) mice were found to have decreased DAT function, i.e., clearance of locally applied DA was decreased by 50% relative to that in D-2(+/+) mice. In D-2(+/+) mice, but not D-2(-/-) mice, local application of the D-2-like receptor antagonist raclopride increased DA signal amplitude, indicating decreased DA clearance. Binding assays with the cocaine analogue [H-3]WIN 35,428 showed no genotypic differences in either density or affinity of DAT binding sites in striatum or substantia nigra, indicating that the differences seen in DAT activity were not a result of decreased DAT expression. These results further strengthen the idea that the D-2 DA receptor subtype modulates activity of the striatal DAT.