(+)-WAY 100135, a partial agonist, at native and recombinant 5-HT1B/1D receptors

1 We have studied the effects of the purportedly selective 5-HT1A receptor antagonist (+)-WAY100135 on electrically stimulated 5-hydroxytryptamine (5-HT) efflux in the ventrolateral geniculate nucleus (vLGN), and its affinity at human 5-HT1B and 5-HT1D receptors stably expressed in Chinese hamster ovary (CHO) cells. 2 On short 'pseudo single pulse' stimulations (20 pulses at 100 Hz, 190 ms train duration), (+)-WAY100135 (1.0 mu M) decreased 5-HT efflux in the vLGN to 68 +/- 8% of pre-drug values (P<0.01). This decrease could be blocked by the 5-HT1D/1B receptor antagonist GR 127935 (50 nM). Conversely, when long stimulations (20 pulses at 20 Hz, 950 ms train) were used, (+)-WAY100135 had no effect on 5-HT efflux (84 +/- 8% of pre-drug values) although both methiothepin (200nM) and GR 127935 (50 nM) caused significant increases (to 175+/-18 and 130+/-10% of pre-drug values, respectively). 3 Paroxetine (100 nM), the selective 5-HT reuptake inhibitor, increased stimulated 5-HT efflux and reuptake half-life (to 145 +/- 18% and 649 +/- 121%, respectively) on pseudo single pulse stimulations. When (+)-WAY 100135 was added in combination with the uptake blocker, the effect of paroxetine on stimulated 5-HT efflux was potentiated to 282+/-48% (P<0.01) without further effect on the 5-HT reuptake half-life. 4 The affinity and intrinsic activity of(+)-WAY 100135 were determined at recombinant human 5-HT1B and 5-HT1D receptors expressed in CHO cells, by use of radioligand binding and [S-35]-GTP gamma S binding. (+)-WAY 100135 was a partial agonist at human 5-HT1B and 5-HT1D receptors with moderately high affinity for 5-HT1D receptors (pEC(50) = 7.61). 5 In conclusion, (+)-WAY 100135 was found to be not a selective 5-HT1A autoreceptor antagonist but may act as a partial agonist at the 5-HT1B/1D receptor, displaying agonist or antagonist properties depending on the stimulation protocol used and the resultant 5-HT 'tone' at the receptor.