Increased affinity of dopamine for D 2 ‐like versus D 1 ‐like receptors. Relevance for volume transmission in interpreting PET findings

Evidence indicates that dopamine (DA) mainly acts as a volume transmission (VT) transmitter through its release into the extracellular fluid where the D 1 ‐like and D 2 ‐like receptors are predominantly extrasynaptic. It was therefore of interest to compare the affinities of the two major families of DA receptors. [ 3 H] raclopride /DA and [ 3 H] SCH23390/DA competition assays compared the affinity of DA at D 2 ‐like and D 1 ‐like receptors in rat dorsal striatal membrane preparations as well as in membrane preparations from CHO cell lines stably transfected with human D 2L and D 1 receptors. The IC 50 values of DA at D 2 ‐like receptors in dorsal striatal membranes and CHO cell membranes were markedly and significantly reduced compared with the IC 50 values of DA at D 1 ‐like receptors. These IC 50 values reflect differences in both the high and low affinity states. The K iH value for DA at [ 3 H] raclopride‐labeled D 2 ‐like receptors in dorsal striatum was 12 nM, and this can help explain PET findings that amphetamine‐induced increases in DA release can produce an up to 50% decrease of [ 11 C] raclopride binding in the dorsal striatum in vivo. These combined results give indications for the existence of striatal D 2 ‐like receptor‐mediated DA VT at the local circuit level in vivo . The demonstration of a K iH value of 183 nM for DA at D 1 antagonist‐labeled D 1 ‐like receptors instead gives a likely explanation for the failure of a reduction of D 1 ‐like receptor binding after amphetamine‐induced DA release in PET studies using the D 1 ‐like antagonist radioligands [ 11 C] SCH23390 and [ 11 C] NNC. It seems difficult to evaluate the role of the extrasynaptic D 1 receptors in VT in vivo with the PET radioligands available for this receptor. Synapse, 2012. © 2011 Wiley Periodicals, Inc.