Assessment of relative efficacies of 5-HT1A receptor ligands by means of in vivo animal models

We have evaluated the effects of ligands with varying efficacies at beta-adrenoceptors and 5-HT1A receptors in three in vivo models reflecting pre- and/or postsynaptic 5-HT1A receptor activation. Forepaw treading in rats is mediated by postsynaptic 5-HT1A receptors, 8-OH-DPAT (8-hydroxy-2-(di-n-propylamin)tetralin)-induced discriminative stimulus is predominantly mediated by postsynaptic, but presynaptic 5-HT1A receptors might also be involved, and footshock-induced ultrasonic vocalization involves predominantly presynaptic 5-HT1A receptors. In vitro receptor binding studies demonstrated high beta-adrenoceptor and 5-HT1A receptor affinity of (-)-penbutolol, high beta-adrenoceptor and 60 times lower 5-HT1A receptor affinity of (+)-penbutolol, high beta-adrenoceptor affinity and about 100 times lower 5-HT1A receptor affinity of pindolol and (-)-tertatolol, only affinity for beta-adrenoceptors of metoprolol and ICI 118,551 (erythro-D,L-1-(7-methylindan-4-yloxy)-3-isopropylamine-butan-2-ol, and only affinity for 5-HT1A receptors of WAY 100.635 ((N-[2-[4-(2-methoxyphenyl)-1 -piperazinyl]ethyl]-N-(2-pyridinyl)cyclo-hexane-carboxamide). (-)-Penbutolol, (-)-tertatolol, pindolol and WAY 100.635 antagonized 5-MeODMT-induced (5-methoxy-N,N-dimethyltryptamine) forepaw treading in rats, and (+)-penbutolol, ICI 118,551 and metoprolol were inactive. (-)-Penbutolol, WAY 100.635 and (-)-tertatolol antagonized 8-OH-DPAT-induced discriminative stimulus in rats, pindolol and metoprolol showed a mixed antagonistic and agonistic profile. Pindolol antagonized footshock-induced ultrasonic vocalization in rats, tertatolol inhibited maximum 36% and WAY 100.635, (-)-penbutolol, (+)-penbutolol, metoprolol and ICI 118,551 were inactive. (-)-Penbutolol and WAY 100.635 reversed 8-OH-DPAT-induced inhibition of ultrasonic vocalization completely, (-)-tertatolol reversed maximum 52% and (+)-penbutolol and pindolol were inactive. It is concluded, that efficacies at 5-HT1A receptors can be estimated by applying a battery of in vivo test models that involve post- and presynaptic receptors to a variable degree. The in vivo ranking order of efficacy at 5-HT1A receptors was: WAY 100.635 =(-)-penbutolol <(-)-tertatolol < pindolol.