In Human Brain Two Subtypes of D1 Dopamine Receptors Can Be Distinguished on the Basis of Differences in Guanine Nucleotide Effect on Agonist Binding

D1 dopamine receptors were identified in membranes of human nucleus caudatus, nucleus accumbens, amygdala, and globus pallidus, by the specific binding of [3H](+)‐R‐8‐chloro‐2,3,4,5‐tetrahydro‐3‐methyl‐5‐phenyl‐lH‐benzazepine‐7‐ol ([3H]SCH 23390). In these four brain regions, dopamine/[3H]SCH 23390 competition binding curves were computer‐analyzed to a two‐site model, distinguishing a high‐ (RH) and low‐ (RL) affinity site for dopamine. The ability of guanine nucleotides (0.4 mM GTP or 0.1 mM 5′‐guanylylimidodiphosphate) to provoke a conversion of RH into RL was different between these brain regions. In amygdala, a complete conversion was seen, whereas there was no guanine nucleotide‐effect on RH in globus pallidus. In nucleus caudatus and nucleus accumbens, guanine nucleotides provoked only a partial conversion of RH into RL, suggesting that these brain regions may contain guanine nucleotide‐sen‐sitive and ‐insensitive receptors. Heating of the membranes at 60°C for 5 min had the same effect as guanine nucleotides. The pharmacological profiles of the guanine nucleotide‐sensitive and ‐insensitive D1 receptors were similar, suggesting that D1 receptors in human brain are heterogeneous only with respect to their effector‐coupling mechanism: guanine nucleotide‐sensitive receptors, which are capable of undergoing functional coupling with Gs, and guanine nucleotide‐insensitive receptors, which are not. A lesion of the cortico‐striatal pathways had no effect on the D1 receptors in nucleus caudatus, whereas a lesion of the mesostriatal pathways resulted in an up‐regulation of the guanine nucleotide‐sensitive, as well as the guanine nucleotide‐insensitive receptors, suggesting that in nucleus caudatus both receptor types are located postsynaptically to the mesostriatal axons, probably on intrinsic striatal neurons.