Article date: June 1997
By: Colin Davidson, Michael Ho, Gary W. Price, Brian J. Jones, Jonathan A. Stamford, in Volume 121, Issue 4, pages 737-742
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.
On short ‘pseudo single pulse’ stimulations (20 pulses at 100 Hz, 190 ms train duration), (+)‐WAY100135 (1.0 μM) 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).
Paroxetine (100 nM), the selective 5‐HT reuptake inhibitor, increased stimulated 5‐HT efflux and re‐uptake 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 re‐uptake half‐life.
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 [35S]‐GTPγS binding. (+)‐WAY 100135 was a partial agonist at human 5‐HT1B and 5‐HT1D receptors with moderately high affinity for 5‐HT1D receptors (pEC50=7.61).
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.
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.
On short ‘pseudo single pulse’ stimulations (20 pulses at 100 Hz, 190 ms train duration), (+)‐WAY100135 (1.0 μM) 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).
Paroxetine (100 nM), the selective 5‐HT reuptake inhibitor, increased stimulated 5‐HT efflux and re‐uptake 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 re‐uptake half‐life.
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 [35S]‐GTPγS binding. (+)‐WAY 100135 was a partial agonist at human 5‐HT1B and 5‐HT1D receptors with moderately high affinity for 5‐HT1D receptors (pEC50=7.61).
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.
British Journal of Pharmacology (1997) 121, 737–742; doi:10.1038/sj.bjp.0701197
DOI: 10.1038/sj.bjp.0701197
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