Effects of the dopamine D-3 antagonist PD 58491 and its interaction with the dopamine D-3 agonist PD 128907 on brain dopamine synthesis in rat

The dopamine (DA) D-3 receptor antagonist PD 58491 {3-[4-[1-[4-[2-[4-(3-diethylaminopropoxy)phenyl]-benzoimidazol-1-yl-butyl]-1H-benzoimidazol-2-yl]phenoxy]propyl]diethylamine} bound with high affinity and selectivity to recombinant human DA D-3 versus D-2L and D-4.2 receptors transfected into Chinese hamster ovary cells: K-i--- values of 19.5 nM versus 2,362 and >3,000 nM, respectively. In contrast, the putative DA D-3 receptor antagonist (+)-AJ76 displayed low affinity and selectivity for D-3 versus D-2L and D-4.2 receptors (91 nM vs. 253 and 193 nM, respectively). In vitro, PD 58491 (1 nM-1 mu M) exhibited D-3 receptor antagonist activity, reversing the quinpirole (10 nM)-induced stimulation of [H-3]thymidine uptake in D-3 CHOpro-5 cells, but did not have any significant intrinsic activity by itself in this assay. PD 58491 did not decrease the gamma-butyrolactone-induced increase in DA synthesis (L-3,4-dihydroxyphenylalanine accumulation) in rat striatum, indicating that the compound possessed no in vivo DA D-2/D-3 receptor agonist action at DA autoreceptors. PD 58491 (3-30 mg/kg, i.p.) generally did not alter DA or serotonin synthesis in either the striatum or mesolimbic region of rat brain. The D-3-preferring agonist PD 128907 decreased DA synthesis in striatum and mesolimbic regions, and this effect was attenuated by pretreatment with PD 58491. These findings support the hypothesis that DA D-3 autoreceptors may in part modulate the synthesis and release of DA in striatum and mesolimbic regions.