INTERACTIONS OF LESOPITRON (E-4424) WITH CENTRAL 5-HT1A RECEPTORS - IN-VITRO AND IN-VIVO STUDIES IN THE RAT

Previous studies have shown that the 5-HT1A receptor ligand, lesopitro n (E-4424, loro-1-pyrazolyl)butyl]-1-piperazinyl]pyrimidine), exerts p otent anxiolytic-like effects in rodents and monkeys (Costall et al., 1992, J. Pharmacol. Exp. Ther. 262, 90). In an attempt to determine wh ether these effects are really mediated through the interaction of les opitron with central 5-HT1A receptors, we investigated the agonistic a nd/or antagonistic nature of this interaction under in vitro and in vi vo conditions in the rat. In vitro binding and autoradiographic studie s with [H-3]8-hydroxy-2-(di-n-propylamino)tetralin ([H-3]8-OH-DPAT) an d [H-3]lesopitron as radioligands confirmed that lesopitron binds to 5 -HT1A receptors in the rat brain with a relatively high affinity (pK(i ) = 7.35). As expected of a full agonist at postsynaptic 5-HT1A recept ors, lesopitron (IC50 = 125 nM) inhibited forskolin-stimulated adenyla te cyclase activity in rat hippocampal membranes to the same extent as 5-HT1A and this effect was preventable by potent 5-HT1A receptor anta gonists such as (-)-tertatolol, (-)-propranolol and -methoxyphenyl)pip erazin-1-yr-2-phenyl-propanamide amide ((+)-WAY 100135). As previously shown for agonists acting at the somato-dendritic 5-HT1A autoreceptor s in the dorsal raphe nucleus, lesopitron inhibited the firing of sero toninergic neurons both in vitro (in brainstem slices, IC50 = 120 nM) and in vivo (in chloral hydrate-anaesthetized rats, ID50 = 35 mu g/kg i.v.), and this effect was preventable by (-)-tertatolol. Interestingl y, the inhibition of the discharge due to Iesopitron lasted for only a few minutes both in vitro and in vivo whereas the anxiolytic-like pro perties of this drug lasted for hours after a single injection in mice (Costall et al., 1992). In addition, the doses required for the stimu lation of pre- and postsynaptic 5-HT1A receptors were markedly higher than those producing significant anxiolytic-like effects in rodents (C ostall et al., 1992). It is therefore unlikely that the anxiolytic-lik e properties of Iesopitron involve its stimulatory action at central 5 -HT1A receptors.