Human platelet 5-hydroxytryptamine receptors: Binding of [3H]-lysergic acid diethylamide (LSD). Effects of chronic neuroleptic and antidepressant drug administration
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Chronic treatment with phenothiazines and thioxanthenes has been found to enhance 5-HT-induced aggregation of human platelets. A method has been developed to study 5-HT2 receptor binding sites on platelets utilising [3H]-LSD and more recently125I/LSD. Results are presented which suggest that the LSD binding site is indeed the 5-HT2 binding site and that the LSD binding characterises the specific receptor responsible for 5-HT-induced shape change and aggregation.
In a group of patients receiving phenothiazines or thioxanthenes, theBmax of LSD binding was increased. The mean binding affinity was decreased possibly due to a persistence of neuroleptic in the platelet membrane preparation. Analysis showed that this was not the reason why the mean binding capacity was increased.
The results show that chronic phenothiazine and thioxanthene δ treatment ‘up-regulates’ platelet 5-HT2 binding sites and that this may be accompanied by increased sensitivity to platelet aggregation by 5-HT.
In normal subjects desipramine treatment increased theBmax of platelet LSD binding and this was accompanied by an increased prolactin response to tryptophan which is thought to be mediated by central 5-HT function.
Key wordsPlatelets 5-HT LSD binding neuroleptics
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- 3.Baldacci, M., Bergel, T. D., Born, G. V. R., and Hickman, M., Increases in aggregation by uptake of 5-hydroxytryptamine with platelets from rabbits treated with chlorpromazine. Br. J. Pharmac. Chemother.69 (1980) 113–118.Google Scholar
- 4.Boullin, D. J., Grahame-Smith, D. G., Grimes, R. P. J., and Woods, H. F., Inhibition of hydroxytryptamine induced human blood platelet aggregation by chlorpromazine and its metabolites. Br. J. Pharmac. Chemother.53 (1975) 121–125.Google Scholar
- 5.Boullin, D. J., Woods, H. F., Grimes, R. P. J., Grahame-Smith, D. G., Wiles, D., Gelder, M. G., and Kolakowska, T., Increased platelet aggregation responses to 5-hydroxytryptamine in patients taking chlorpromazine. Br. J. clin. Pharmac.2 (1975) 29–35.Google Scholar
- 6.Boullin, D. J., Orr, M. W., and Peters, J. R., The platelet as a model for investigating clinical efficacy of centrally acting drugs: relations between platelet aggregation and clinical condition in schizophrenics treated with chlorpromazine, in: Platelets: a Multi-disciplinary Approach. Eds S. E. de Gaetano and S. Gorathine. Raven Press, New York 1978.Google Scholar
- 7.Boullin, D. J., Knox, J. M., Peters, J., and Orr, M., Platelet aggregation and chlorpromazine therapy. Br. J. clin. Pharmac.6 (1978) 538–540.Google Scholar
- 8.Cowen, P. J., and Anderson, I. M., in: Recent advances in the biology of depression. Eds. J. F. W. Deakin and H. Freeman. Royal College of Psychiatrists, special publication, 1986.Google Scholar
- 9.Cowen, P. J., Geaney, D. P., Schacter, M., Green, A. R., and Elliott, M. J., Desipramine treatment in normal subjects effects on neuroendocrine response to tryptophan and on platelet serotonin (5-HT)-related receptors. Archs gen. Psychiat.43 (1986) 61–67.Google Scholar
- 10.Cross, A. J., Interactions of [3H]-LSD with serotonin receptors in human brain. Eur. J. Pharmac.82 (1982) 77.Google Scholar
- 11.Dawbarn, D., Long, S. K., and Pycock, C. J., Increased central 5-hydroxytryptamine receptor mechanisms in rats after chronic neuroleptic treatment. Br. J. Pharmac. Chemother.73 (1981) 149–156.Google Scholar
- 12.Geaney, D. P., Schacter, M., Elliott, J. M., and Grahame-Smith, D. G., Characterization of [3H]-Lysergic acid diethylamide binding to a 5-hydroxytryptamine receptor on human platelet membranes. Eur. J. Pharmac.97 (1984) 87–93.Google Scholar
- 14.Hefez, A., Oppenheim, B., and Youdim, M. B. H., Human platelet aggregation response to serotonin as an index of efficacy of chlorpromazine, in: Enzymes and Neurotransmitters in Mental Disease, pp. 77–93. Eds E. Usdin, T. L. Sourkes and M. B. H. Youdim. John Wiley, New York 1980.Google Scholar
- 15.Knox, J. M., Orr, M. W., Allen, R., Gelder, M. G., and Grahame-Smith, D. G., The reliability of 5-hydroxytryptamine reduced platelet aggregation responses in schizophrenic patients with neuroleptic drugs. Br. J. clin. Pharmac.11 (1981) 261–263.Google Scholar
- 17.Laubscher, A., Pletscher, A., and Noll, H., Interaction ofd-LSD with blood platelets of rabbits: shape, change and specific binding. J. Pharmac. exp. Ther.216 (1981) 385.Google Scholar
- 18.Leysen, J. E., Commeren, W., and de Clerck, F., Demonstration of S2-receptor binding sites in cat platelets using [3H]-ketanserin. Eur. J. Pharmac.88 (1983) 125–130.Google Scholar
- 19.Mills, D. C. B., and Roberts, G. C. K., Membrane active drugs and the aggregation of human blood platelets. Nature213 (1967) 35–38.Google Scholar
- 20.Orr, M. W., and Boullin, D. J., The relationship between changes in 5-HT induced platelet aggregation and the clinical state in patients treated with fluphenazine. Br. J. clin. Pharmac.3 (1976) 925–928.Google Scholar
- 21.Orr, M. W., Knox, J. M., Allen, R., Gelder, M. G., and Grahame-Smith, D. G., The effects of neuroleptic drugs on 5-hydroxytryptamine induced platelet aggregation in schizophrenic patients. Br. J. clin. Pharmac.11 (1981) 255–259.Google Scholar
- 22.Peroutka, S. J., and Snyder, S. H., Multiple serotonin receptors differential binding of [3H]-5-hydroxytryptamine, [3H]-lysergic acid diethylamide and [3H]-spiroperidol. Molec. Pharmac.16 (1979) 687–698.Google Scholar
- 24.Peters, J. R., and Grahame-Smith, D. G., Human platelet 5-HT receptors: characterisation and functional association. Eur. J. Pharmac.68 (1980) 243.Google Scholar
- 25.Schacter, M., Geaney, D. P., Grahame-Smith, D. G., Cowen, P., and Elliott, J. M., Increased platelet membrane [3H]-LSD binding in patients on chronic neuroleptic treatment. Br. J. clin. Pharmac.19 (1985) 453–457.Google Scholar