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Journal List > Br J Pharmacol > v.121(4); Jun 1997
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PubMed articles by:
Davidson, C.
Ho, M.
Price, G.
Stamford, J.
Br J Pharmacol. 1997 June; 121(4): 737–742.
doi: 10.1038/sj.bjp.0701197.
PMCID: PMC1564750
Copyright 1997, Nature Publishing Group
(+)-WAY 100135, a partial agonist, at native and recombinant 5-HT1B/1D receptors
Colin Davidson,1 Michael Ho,* Gary W Price,* Brian J Jones,* and Jonathan A Stamford*
Anaesthetics Unit (Neurotransmission Laboratory), St Bartholomew's and the Royal London School of Medicine and Dentistry, Alexandra Wing, Royal London Hospital, Whitechapel, London E1 1BB
*SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Harlow, Essex, CM19 5AW
*Author for correspondence:
1Present address: School of Psychology, University of St Andrews, Fife, KY16 9JU
Received November 18, 1996; Revised March 12, 1997; Accepted March 19, 1997.
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Abstract
  • 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.
Keywords: Lateral geniculate nucleus, 5-hydroxytryptamine (5-HT), 5-HT1B/1D autoreceptor, (+)-WAY100135, fast cyclic voltammetry, partial agonist, [35S]-GTPγS binding
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