Effects of the Dopamine D3 Antagonist PD 58491 and Its Interaction with the Dopamine D3 Agonist PD 128907 on Brain Dopamine Synthesis in Rat

: The dopamine (DA) D3 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 D3 versus D2L and D4.2 receptors transfected into Chinese hamster ovary cells: Ki values of 19.5 nM versus 2,362 and >3,000 nM, respectively. In contrast, the putative DA D3 receptor antagonist (+)‐AJ76 displayed low affinity and selectivity for D3 versus D2L and D4.2 receptors (91 nM vs. 253 and 193 nM, respectively). In vitro, PD 58491 (1 nM−1µM) exhibited D3 receptor antagonist activity, reversing the quinpirole (10 nM)‐induced stimulation of [3H]thymidine uptake in D3 CHOpro‐5 cells, but did not have any significant intrinsic activity by itself in this assay. PD 58491 did not decrease the γ‐butyrolactone‐induced increase in DA synthesis (l‐3,4‐dihydroxyphenylalanine accumulation) in rat striatum, indicating that the compound possessed no in vivo DA D2/D3 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 D3‐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 D3 autoreceptors may in part modulate the synthesis and release of DA in striatum and mesolimbic regions.