Dopamine D2 Receptor‐Deficient Mice Exhibit Decreased Dopamine Transporter Function but No Changes in Dopamine Release in Dorsal Striatum

: Presynaptic D2 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 D2 DA receptor deficiency on DA release and DAT activity in dorsal striatum, we used mice genetically engineered to have two (D2+/+), one (D2+/‐), or no (D2‐/‐) functional copies of the gene coding for the D2 DA receptor. In vivo microdialysis studies demonstrated that basal and K+‐evoked extracellular DA concentrations were similar in all three genotypes. However, using in vivo electrochemistry, the D2‐/‐ mice were found to have decreased DAT function, i.e., clearance of locally applied DA was decreased by 50% relative to that in D2+/+ mice. In D2+/+ mice, but not D2‐/‐ mice, local application of the D2‐like receptor antagonist raclopride increased DA signal amplitude, indicating decreased DA clearance. Binding assays with the cocaine analogue [3H]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 D2 DA receptor subtype modulates activity of the striatal DAT.