Low affinity binding of the classical D1 antagonist SCH23390 in rodent brain: potential interaction with A2A and D2-like receptors.
Whereas structurally dissimilar D(1) antagonists competing for [(3)H]-SCH23390 binding recognize primarily one site in striatum, two distinct affinity states are observed in both amygdala and hippocampus. The binding profile of SCH23390 is similar in both of these regions, with the high affinity site (K(D) approximately 0.4 nM) consistent with D(1)/D(5) receptors. The appearance of the low affinity site (K(D) approximately 300 nM) is dependent upon the absence of MgCl(2), but independent of D(1) expression (i.e., still present in D(1) knockout mice). Although the density of high affinity state receptor is lower in hippocampus or amygdala of D(1) knockout mice, some residual binding remains, consistent with the known expression of D(5) receptors in these regions. Remarkably, in hippocampus, the affinity of the low affinity site is shifted rightward in the presence of the D(2) antagonist domperidone and is largely absent in the hippocampus of D(2) knockout animals. Additionally, this site is also shifted rightward in the presence of the A(2A) ligands SCH58261, CSC, or NECA, or in the absence of A(2A) receptors. The affinity of SCH23390 for this low affinity site is greater than seen for SCH23390 binding to D(2) receptors in heterologous expression systems, consistent with the hypothesis that both D(2) and A(2A) receptors are involved in the low affinity binding site. Therefore, we suggest that the heteromerization of D(2) and A(2A) receptors reported previously in vitro also may occur in the brain of both rats and mice.
Leonard
Sarah K
SK
Department of Pharmacology, CB #7160, 7011 NC Neurosciences Hospital, University of North Carolina, School of Medicine, Chapel Hill, NC 27599-7160, USA.
Ferry-Leeper
Penelope
P
Mailman
Richard B
RB
D000241:Adenosine / Q000378:metabolism; D000818:Animals; D001552:Benzazepines / Q000378:metabolism* / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics; D001667:Binding, Competitive / Q000187:drug effects / Q000235:genetics; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism; D004294:Domperidone / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006367:HeLa Cells; D006801:Humans; D015636:Magnesium Chloride / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011869:Radioligand Assay; D051381:Rats; D011940:Receptor Aggregation / Q000187:drug effects / Q000235:genetics; D043705:Receptor, Adenosine A2A / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism
D001552:Benzazepines; D018492:Dopamine Antagonists; D043705:Receptor, Adenosine A2A; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D015636:Magnesium Chloride; D004294:Domperidone; D000241:Adenosine; D004298:Dopamine