Increased affinity of dopamine for D2-like versus D1-like receptors. Relevance for volume transmission in interpreting PET findings

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Evidence indicates that dopamine (DA) mainly acts as a volume transmission (VT) transmitter through its release into the extracellular fluid where the D1-like and D2-like receptors are predominantly extrasynaptic. It was therefore of interest to compare the affinities of the two major families of DA receptors. [3H] raclopride /DA and [3H] SCH23390/DA competition assays compared the affinity of DA at D2-like and D1-like receptors in rat dorsal striatal membrane preparations as well as in membrane preparations from CHO cell lines stably transfected with human D2L and D1 receptors. The IC50 values of DA at D2-like receptors in dorsal striatal membranes and CHO cell membranes were markedly and significantly reduced compared with the IC50 values of DA at D1-like receptors. These IC50 values reflect differences in both the high and low affinity states. The KiH value for DA at [3H] raclopride-labeled D2-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 [11C] raclopride binding in the dorsal striatum in vivo. These combined results give indications for the existence of striatal D2-like receptor-mediated DA VT at the local circuit level in vivo. The demonstration of a KiH value of 183 nM for DA at D1 antagonist-labeled D1-like receptors instead gives a likely explanation for the failure of a reduction of D1-like receptor binding after amphetamine-induced DA release in PET studies using the D1-like antagonist radioligands [11C] SCH23390 and [11C] NNC. It seems difficult to evaluate the role of the extrasynaptic D1 receptors in VT in vivo with the PET radioligands available for this receptor. Synapse, 2012. © 2011 Wiley Periodicals, Inc.

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