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Diazepam alters brain 5-HT function in man: implications for the acute and chronic effects of benzodiazepines

Published online by Cambridge University Press:  09 July 2009

D. J. Nutt  and
P. J. Cowen
D. J. Nutt*
Affiliation:
University Department of Psychiatry, Warneford Hospital, Oxford and MRC Clinical Pharmacology Unit, Research Unit, Littlemore Hospital, Oxford
P. J. Cowen
Affiliation:
University Department of Psychiatry, Warneford Hospital, Oxford and MRC Clinical Pharmacology Unit, Research Unit, Littlemore Hospital, Oxford
*
1Address for correspondence: Dr D. J. Nutt, National Institute on Alcohol Abuse & Alcoholism, Building 10, Room 3B19, 9000 Rockville Pike, Bethesda, Maryland 20892, USA
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Synopsis

The effect of diazepam on brain 5-HT-mediated neuroendocrine responses was studied in healthy male volunteers. An acute dose of diazepam (15 mg) significantly attenuated the prolactin and growth hormone responses to intravenous L-tryptophan. After 3 weeks administration of diazepam (25 mg/d) these responses had returned to normal despite much higher plasma diazepam concentrations, suggesting that tolerance had occurred. A reduction in brain 5-HT function may underlie some of the acute therapeutic actions of benzodiazepines. It is possible that excessive ‘rebound’ 5-HT activity may contribute to the abstinence syndrome seen on benzodiazepine withdrawal.

Type
Research Article
Information
Psychological Medicine , Volume 17 , Issue 3 , August 1987 , pp. 601 - 607
Copyright
Copyright © Cambridge University Press 1987

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References

Adam, K., Adamson, L., Brezinova, V. L., Hunter, W. M. & Oswald, I. (1976). Nitrazepam: lastingly effective but trouble on withdrawal. British MedicalJoumal i, 1558–1560.CrossRefGoogle Scholar
Anderson, I. M. & Cowen, P. J. (1986). Clomipramine enhances prolactin and growth hormone responses to l-tryptophan. Psychopharmacology 89, 131–133.CrossRefGoogle ScholarPubMed
Ashton, H. (1984). Benzodiazepine withdrawal: an unfinished story. British Medical Journal 288, 1135–1140.CrossRefGoogle ScholarPubMed
Braestrup, C., Nielsen, M. & Squires, R. F. (1979). No changes in rat benzodiazepine receptors after withdrawal from continuous treatment with lorazepam and diazepam. Life Science 24, 347–350.CrossRefGoogle ScholarPubMed
Braestrup, C., Nielsen, M., Honore, T., Jensen, L. H. & Petersen, E. N. (1983). Benzodiazepine-GABA receptor-ionophore complex. Current concepts. Neuropharmacology 22, 1451–1458.CrossRefGoogle Scholar
Charney, D. S., Heninger, G. R., Renhard, J. F., Sternberg, D. E. & Hafstead, K. M. (1982). Effect of intravenous l-tryptophan on prolactin and growth hormone and mood in healthy subjects. Psychopharmacology 77, 217–222.CrossRefGoogle ScholarPubMed
Collinge, J., Pycock, C. J. & Taberner, P. V. (1983). Studies on the interaction between cerebral 5-hydroxytryptamine and gammaaminobutyric acid in the mode of action of diazepam in the rat. British Journal of Pharmacology 79, 637–643.CrossRefGoogle ScholarPubMed
Conover, W. J. & Iman, R. L. (1981). Rank informations as a bridge between parametric and non-parametric statistics. The American Statistician 35, 124–129.CrossRefGoogle Scholar
Corrodi, H., Fuxe, K., Lidbrink, P. & Olsen, L. (1971). Minor tranquillizers, stress and central catecholamine neurons. Brain Research 29, 1–16.CrossRefGoogle ScholarPubMed
Covi, L., Lipman, R. S., Pattison, J. H., Derogatis, L. R. & Uhlenhuth, E. H. (1973). Length of treatment with anxiolytic sedatives and response to their sudden withdrawal. Acta Psychiatrica Scandinavica 49, 51–64.CrossRefGoogle ScholarPubMed
Cowen, P. J., Gadhvi, H., Gosden, B. & Kolakowska, T. (1985). Responses of prolactin and growth hormone to l-tryptophan infusion: effects in normal subjects and schizophrenic patients receiving neuroleptics. Psychopharmacology 86, 164–169.CrossRefGoogle ScholarPubMed
Curzon, G. (1979). Relationships between plasma, CSF and brain tryptophan. Journal of Neural Transmission 15, 81–92.Google Scholar
Denckla, W. D. & Dewey, H. K. (1961). The determination of tryptophan in plasma liver and urine. Journal of Laboratory and Clinical Medicine 69, 160–169.Google Scholar
Feely, M., Calvert, R. & Gibson, J. (1982). Clobazam in catamenial epilepsy: a model for evaluating anticonvulsants. Lancet ii, 71–73.CrossRefGoogle Scholar
Fontaine, R., Chouinard, G. & Annable, L. (1984). Rebound anxiety in anxious patients after abrupt withdrawal of benzodiazepine treatment. Amerian Journal of Psychiatry 141, 848–852.Google ScholarPubMed
Gillman, P. K., Bartlett, J. R., Bridges, P. K., Hunt, A., Patel, A. J., Kantameneni, B. D. & Curzon, G. (1981). Indolic substances in plasma CSF and frontal cortex or human subjects infused with saline or l-tryptophan. Journal of Neurochemistry 37, 410–417.CrossRefGoogle ScholarPubMed
Grandison, L. (1983). Actions of benzodiazepines on the neuroendocrine system. Neuropharmacology 22, 1505–1510CrossRefGoogle ScholarPubMed
Greenblatt, D. J., Woo, E., Allen, M. D., Orsulak, P. J. & Shader, R. I. (1978). Rapid recovery from massive diazepam overdose. Journal of American Medical Association 240, 1872–1874.CrossRefGoogle ScholarPubMed
Hallstrom, C. (1985). Benzodiazepines: clinical practice and central mechanisms. In Recent Advances in Clinical Psychiatry (ed. Grossman, K.), pp. 143–159. Churchill Livingstone: London.Google Scholar
Jones, R. L. & Luscombe, D. K. (1976). Plasma levels of clomipramine and its N-desmethyl metabolite following oral clomipramine in man. British Journal of Pharmacology 57, 430P.Google ScholarPubMed
Linnoila, M., Virkkunen, M., Scheinin, M., Nuutila, A., Rimon, R. & Goodwin, F. K. (1983). Low cerebrospinal fluid 5-hydroxyindoleacetic acid concentration differentiates impulse from non-impulsive violent behaviour. Life Sciences 33, 2609–2614.CrossRefGoogle Scholar
Lister, R. G. & File, S. E. (1983). Changes in regional concentrations in the rat brain of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid during the development of tolerance to the sedative action of chlordiazepoxide. Journal of Pharmacy and Pharmacology 35, 601–603.CrossRefGoogle Scholar
Macindoe, J. H. & Turkington, R. W (1973). Stimulation of human prolactin secretion by intravenous infusion of l-tryptophan. Journal of Clinical Investigation 52, 1972–1978.CrossRefGoogle ScholarPubMed
Meites, J. & Sonntag, W E. (1981). Hypothalamic, hypophysiotropic hormones and neurotransmitter regulation: current views. Annual Review of Pharmacology and Toxicology 21, 295–322.CrossRefGoogle ScholarPubMed
Meltzer, H. Y., Wiita, B., Tricou, B. J., Simonovic, M., Fang, U. S. & Manov, G. (1981). Effects of serotonin precursors and serotonin agonists on plasma hormone levels. In Serotonin in Biological Psychiatry (ed. Ho, B. T., Schooler, J. C. and Usdin, E.), pp. 117–139. Raven Press: New York.Google Scholar
Moir, A. T. B. & Eccleston, D. (1968). The effects of precursor loading in the cerebral metabolism of 5-hydroxyindoles. Journal of Neurochemistry 15, 1093–1108.CrossRefGoogle ScholarPubMed
Mueller, E. A., Murphy, D. L., Sunderland, T. & Jones, J. (1985). A new post-synaptic serotonin receptor agonist suitable for studies in humans. Psychopharmacology Bulletin 21, 701–704.Google Scholar
Nutt, D. J., Cowen, P. J., Franklin, M., Murdock, P., Gosden, B. & Fraser, S. (1986 a). The effect of diazepam on indices of 5-HT function in man. Pharmacology, Biochemistry & Behaviour 24, 1491–1495.CrossRefGoogle ScholarPubMed
Nutt, D. J., Franklin, M., Gosden, B. & Murdock, P. (1986 b). The effect of diazepam on indices of alpha-adrenoceptor function in man. British Journal of Clinical Pharmacology 21, 588.Google Scholar
Olsen, R. W. (1981). GABA-benzodiazepine-barbiturate receptor interactions. Journal of Neurochemistry 37, 1–13.CrossRefGoogle ScholarPubMed
Pardridge, W. M. (1979). The role of the blood-brain barrier transport of tryptophan and other neutral amino acids in the regulation of substrate-limited pathways of brain amine acid metabolism. Journal of Neural Transmission 15, 43–54.Google Scholar
Petursson, H. & Lader, M. H. (1981). Withdrawal from long-term benzodiazepine treatment. British Medical Journal 283, 643–645.CrossRefGoogle ScholarPubMed
Petursson, H. & Lader, M. H. (1984). Dependence on Tranquillizers. Oxford University Press: Oxford.Google Scholar
Petursson, H., Shur, E., Checkley, S., Slade, A. & Lader, M. H. (1981). A neuroendocrine approach to benzodiazepine tolerance and dependence. British Journal of Clinical Pharmacology 11, 526–528.CrossRefGoogle ScholarPubMed
Petursson, H., Bond, P. A., Smith, B. & Lader, M. H. (1983). Monoamine metabolism during chronic benzodiazepine treatment and withdrawal. Biological Psychiatry 18, 207–213.Google ScholarPubMed
Preziosi, P. (1983). Serotonin control of prolactin release: an intriguing puzzle. Trends Pharmacological Science 4, 171–174.CrossRefGoogle Scholar
Quattrone, A., Tedeschi, A., Aguglia, U., Scopacasa, F., Direnzo, G. F. & Annunziato, L. (1983). Prolactin secretion in man: a useful tool to evaluate the activity of drugs on central 5-hydroxytryptaminergic neurones: studies with fenfluramine. British Journal of Clinical Pharmacology 16, 471–475.CrossRefGoogle Scholar
Rastogi, R. B., Lapierre, Y. D. & Singhal, R. L. (1976). Evidence for the role of brain norepinephrine and dopamine in ‘rebound’ phenomena seen during withdrawal after repeated exposure to benzodiazepines. Journal of Psychiatry Research 13, 65–75.CrossRefGoogle Scholar
Rickels, K. & Downing, R. W. (1966). Drug and placebo treated neurotic outpatients. Archives of General Psychiatry 16, 369–372.CrossRefGoogle Scholar
Taylor, K. M. & Laverty, R. (1969). The effect of chlordiazepoxide, diazepam and nitrazepam on catecholamine metabolism in regions of rat brain. European Journal of Pharmacology 8, 296–301.CrossRefGoogle ScholarPubMed
Thiebot, M. H.Le Bihan, C., Soubrie, P. & Simon, P. (1985) Benzodiazepines reduce the tolerance to reward delay in rats. Psychopharmacology 86, 147–152.CrossRefGoogle Scholar
Trulson, M. E., Preussler, D. W., Howell, G. A. & Frederickson, C. J. (1982). Raphe unit activity in freely moving cats: effects of benzodiazepines. Neuropharmacology 21, 1045–1050.CrossRefGoogle ScholarPubMed
Tuomisto, J. & Mannisto, P. (1985). Neurotransmitter regulation of anterior pituitary hormones. Pharmacological Reviews 37, 249–332.Google ScholarPubMed
Tyrer, P., Owen, R. & Dawling, S. (1983). Gradual withdrawal of diazepam after long-term therapy. Lancet i, 1402–1406.CrossRefGoogle Scholar
Wise, C. D., Berger, B. D. & Stein, L. (1972). Benzodiazepines: anxiety-reducing activity by reduction of serotonin turnover in the brain. Science 177, 180–183.CrossRefGoogle ScholarPubMed