Characterization of MDL 73005EF as a 5‐HT1A selective ligand and its effects in animal models of anxiety: comparison with buspirone, 8‐OH‐DPAT and diazepam

1 With radioligand binding techniques, MDL 73005 EF (8‐[2‐(2,3‐dihydro‐1,4‐benzodioxin‐2‐yl‐methylamino)ethyl]‐8‐azaspiro[4,5]decane‐7,9‐dione methyl sulphonate) shows high affinity (pIC50 8.6) and selectivity (>100 fold compared to other monoamine and benzodiazepine receptor sites) for the 5‐hydroxytryptamine (5‐HT)1A recognition site; it was both more potent and more selective than buspirone in this respect. 2 In rats pretreated with reserpine, 8‐hydroxy‐2‐(di‐n‐propyl‐amino) tetralin (8‐OH‐DPAT) induced forepaw treading and flat body posture; in the same model, MDL 73005EF and buspirone showed minimal agonist activity and at high doses MDL 73005EF inhibited responses to 8‐OH‐DPAT. 3 In rats trained to discriminate 8‐OH‐DPAT from saline in a drug discrimination paradigm, both MDL 73005EF and buspirone generalized dose‐dependently and completely to the 8‐OH‐DPAT cue. 4 To define the anxiolytic potential of MDL 73005EF, it was examined in the elevated plus‐maze test and in the water‐lick conflict test in comparison with diazepam and buspirone. In both tests MDL 73005EF induced effects similar to those seen following diazepam. Buspirone had similar effects to both MDL 73005EF and diazepam in the water‐lick conflict test but opposite effects in the elevated plus‐maze. 8‐OH‐DPAT also had opposite effects in the elevated plus‐maze test to MDL 73005EF and diazepam. 5 The anti‐conflict effects of MDL 73005EF were reversed by low doses of the 5‐HT1A receptor agonist, 8‐OH‐DPAT; those of buspirone were neither antagonised nor mimicked by 8‐OH‐DPAT. 6 These results suggest that an interaction with 5‐HT1A receptors is the basis of the anxiolytic‐like activity of MDL 73005EF. However, its mechanism of action is clearly different from that of buspirone, possibly reflecting a greater selectivity for the 5‐HT1A receptors located presynaptically on central 5‐hydroxytryptaminergic neurones.