The potent 5-HT3 receptor antagonist (R)-zacopride labels an additional high affinity site in the central nervous system

The binding characteristics of [3H](S)-zacopride were investigated in membranes from the rat entorhinal cortex and NG 108-15 clonal cells. In contrast to [3H](S)-zacopride which bound solely to 5-HT3 receptors, [3H](R)-zacopride recognized another class of binding sites, called the (R)-sites, in both membrane preparations. In addition to (R)-zacopride (Ki=3–11 nM), only (R)-iodo-zacopride, (R)-dechloro-zacopride, prazosin and mianserin exhibited high to moderate affinity for the (R)-sites, whose possible functions remain to be established

Evidence for 5-HT(1B/1D) and 5-HT(2A) receptors mediating constriction of the canine internal carotid circulation

1. The present study has investigated the preliminary pharmacological profile of the receptors mediating vasoconstriction to 5-hydroxytryptamine (5-HT) in the internal carotid bed of vagosympathectomised dogs. 2. One minute intracarotid infusions of the agonists 5-HT (0.1–10 μg min(−1)), sumatriptan (0.3–10 μg min(−1); 5-HT(1B/1D)), 5-methoxytryptamine (1–100 μg min(−1); 5-HT(1), 5-HT(2), 5-HT(4), 5-ht(6) and 5-HT(7)) or DOI (0.31–10 μg min(−1); 5-HT(2)), but not 5-carboxamidotryptamine (0.01–0.3 μg min(−1); 5-HT(1), 5-ht(5A) and 5-HT(7)), 1-(m-chlorophenyl)-biguanide (mCPBG; 1–1000 μg min(−1); 5-HT(3)) or cisapride (1–1000 μg min(−1); 5-HT(4)), resulted in dose-dependent decreases in internal carotid blood flow, without changing blood pressure or heart rate. 3. The vasoconstrictor responses to 5-HT, which remained unaffected after saline, were resistant to blockade by i.v. administration of the antagonists ritanserin (100 μg kg(−1); 5-HT(2A/2B/2C)) in combination with tropisetron (3000 μg kg(−1); 5-HT(3/4)) or the cyclo-oxygenase inhibitor, indomethacin (5000 μg kg(−1)), but were abolished by the 5-HT(1B/1D) receptor antagonist, GR127935 (30 μg kg(−1)). Interestingly, after administration of GR127935, the subsequent administration of ritanserin unmasked a dose-dependent vasodilator component. GR127935 or saline did not practically modify the vasoconstrictor effects of 5-MeO-T. In animals receiving GR127935, the subsequent administration of ritanserin abolished the vasoconstrictor responses to 5-MeO-T unmasking a dose-dependent vasodilator component. 4. The vasoconstriction induced by sumatriptan was antagonized by GR127935, but not by ritanserin. Furthermore, ritanserin (100 μg kg(−1)) or ketanserin (100 μg kg(−1); 5-HT(2A)), but not GR127935, abolished DOI-induced vasoconstrictor responses. 5. The above results suggest that 5-HT-induced internal carotid vasoconstriction is predominantly mediated by 5-HT(1B/1D) and 5-HT(2A) receptors