Non-alcoholic fatty liver disease and mortality among US adults: prospective cohort study

The benzopyranopyrrole S33084 displayed pronounced affinity (pK_i = 9.6) for cloned human hD₃-receptors, and >100-fold lower affinity for hD₂ and all other receptors (>30) examined. S33084 concentration dependently, potently, and competitively (pA₂ = 9.7) antagonized dopamine (DA)-induced [³⁵S]guanosine-5′-O-(3-thio)triphosphate (GTPγS) binding at hD₃-receptors. It also concentration dependently abolished stimulation by DA of hD₃-receptor-coupled mitogen-activated protein kinase. Administered alone, S33084 did not modify dialysate levels of DA in the frontal cortex, nucleus accumbens, or striatum of freely moving rats, nor the firing rate of ventrotegmental dopaminergic cell bodies. Furthermore, it had minimal effect on DA turnover in mesocortical, mesolimbic, and nigrostriatal projection regions. However, S33084 dose dependently blocked the suppressive influence of the preferential D₃-agonist PD128,907 on frontocortical release of DA. Furthermore, it likewise antagonized the inhibitory influence of PD128,907 on the electrical activity of ventrotegmental dopaminergic neurons. Although less potent than S33084, GR218,231 likewise behaved as a selective hD₃- versus hD₂-receptor antagonist and its neurochemical and electrophysiological profiles were similar. In contrast, L741,626 was a preferential antagonist at hD₂ versus hD₃sites. In vivo, on administration alone, L741,626 increased frontocortical, mesolimbic, and (more potently) striatal DA release, enhanced the firing rate of dopaminergic perikarya, and accelerated cerebral DA synthesis. It also blocked the actions of PD128,907. In conclusion, S33084 is a novel, potent, selective, and competitive antagonist at hD₃-receptors. Although GR218,231 behaves similarly, L741,626 is a preferential D₂-receptor antagonist. DA D₂- but not D₃-(auto) receptors tonically inhibit ascending dopaminergic pathways, although the latter may contribute to phasic suppression of DA release in frontal cortex.