Dual activation by lisuride of central serotonin 5-HT(1A) and dopamine D(2) receptor sites: drug discrimination and receptor binding studies

To investigate central serotonergic (5-HT) and dopaminergic (DA) actions of lisuride, the discriminative properties of lisuride (0.05mg/kg, i.p.) in rats were investigated, in addition to the radioligand binding of the compound to 5-HT and DA receptor subtypes. Lisuride was found to possess high affinities for 5-HT(1A) receptor sites (Ki=0.5nM) and D(2) receptor sites (Ki=2.0nM). The autoradiographic binding pattern of 4nM [(3)H]lisuride in rat brain showed high densities of sites displaceable by the 5-HT(1A) agonist 8-OH-DPAT in hippocampus, lateral septal nucleus and amygdala, as well as those displaceable by the D(2) antagonist sulpiride in striatum, nucleus accumbens and olfactory tubercle. In drug discrimination tests, the mixed, D(1)/D(2) agonist apomorphine, the partial D(2) receptor agonists (-)-3-PPP and terguride and the 5-HT(1A) agonist 8-OH-DPAT substituted for lisuride. The D(1) agonist SKF38393, the D(1) antagonist SCH23390, the D(2) antagonist sulpiride, the 5HT(1B) agonist m-CPP and the 5-HT(2) agonist DOI were not generalized to the lisuride cue. In antagonism tests, the D(2) antagonist haloperidol and the 5-HT antagonist methysergide both induced partial but significant antagonism to the lisuride cue, but the D(1) antagonist SCH23390 did not. These results indicate that discriminative stimulus properties of lisuride are mediated by the dual activation of 5-HT(1A) and D(2) receptor sites in brain.