The preferential dopamine D3 receptor agonist cis-8-OH-PBZI induces limbic Fos expression in rat brain

Abstract The affinity, selectivity and agonistic properties of a constrained dopaminergic compound, the benz[e]indole cis -8-hydroxy-3-( n -propyl)1,2,3a,4,5,9b-hexahydro-1H-benz[e]indole ( cis -8-OH-PBZI), for the dopamine D 3 receptor were evaluated in competition binding experiments with cloned human dopamine receptor subtypes and, to further extend its profile, in in vitro radioligand binding assays. The K i value measured for competition binding of this compound to the dopamine D 3 receptor was 27.4±3.1 nM; this was 775-fold, 550-fold, 90-fold and 10-fold higher affinity than that measured at dopamine D 1A , D 5 , D 2s and D 4 receptors, respectively. Evidence of dopamine receptor activation by cis -8-OH-PBZI was obtained by measuring dose-dependent increases in extracellular acidification rates and decreases in cAMP synthesis. In vivo, cis -8-OH-PBZI potently induced Fos protein immunoreactivity in the rat medial prefrontal cortex and shell region of the nucleus accumbens, but only marginally in the motor dorsolateral striatum, indicating a selective limbic site of action. In conclusion, the present data identify cis -8-OH-PBZI as having preference for the dopamine D 3 receptor in vitro, and as having dopamine agonist activity and limbic sites of action in vivo.