The actions of diverse antipsychotics at cloned h5-HT(1B) and h5-HT(1D) receptors were examined employing [3H]-GR125,743 and [35S]-GTPgammaS for determination of affinities and efficacies, respectively. Compared with hD(2) receptors, haloperidol, chlorpromazine and olanzapine showed markedly (>100-fold) lower affinity for h5-HT(1D) and h5-HT(1B) receptors at which they expressed inverse agonist properties. Clozapine, risperidone and ocaperidone likewise behaved as inverse agonists at h5-HT(1B) and h5-HT(1D) receptors but their affinities were only approximately 10-fold lower than at hD(2) receptors. Moreover, ziprasidone, S16924 and ORG5222 interacted at h5-HT(1B) and h5-HT(1D) receptors with affinities similar to hD(2) sites. While S16924 and ORG5222 were inverse agonists at h5-HT(1B) and h5-HT(1D) sites, ziprasidone was an inverse agonist at h5-HT(1D) receptors yet a partial agonist at h5-HT(1B) receptors. These actions of antipsychotics were abolished by the selective, neutral antagonist, S18127. In conclusion, with the exception of ziprasidone, all antipsychotics were inverse agonists at h5-HT(1B) and h5-HT(1D) receptors, although they differed markedly in their potency at these sites as compared to hD(2) receptors.