Summary
Administration of a single dose (10 mg/kg) of a relatively new benzodiazepine, bromazepam to rats markedly suppressed their spontaneous locomotor activity. Hypomobility became apparent 15 min after the injection and remained significantly lower during the period of observation for 6 hours when locomotor activity was 27% of controls. Following 2 hours after bromazepam treatment, no change was noted in tyrosine levels and tyrosine hydroxylase activity in striatum or rate of catecholamine synthesis in synaptosomal preparation (P2 pellet). However, the endogenous levels of norepinephrine, dopamine and 5-hydroxytryptamine were significantly increased not only in several brain areas examined, but also in p2 pellet. Bromazepam failed to change3H-norepinephrine and3H-5-hydroxy-tryptamine uptake in synaptosomes suggesting that the increased levels of monoamines are not related to alterations in uptake mechanisms, but probably to a diminished release. This is supported by the data on striatal homovanillic acid and whole brain 4-hydroxy-3-methoxyphenyl glycol whose concentrations were significantly lowered following a single injection of this benzodiazepine. However, bromazepam increased 5-hydroxyindoleacetic acid levels in hypothalamus, mid-brain and pons-medulla. The present study demonstrates that bromazepam elicits its tranquilizing action by lowering the release of catecholamines in brain; however, its anti-anxiety action might be associated with a reduction in 5-hydroxytryptamine turnover. Our data also suggest that bromazepam is almost as potent as diazepam in altering the metabolism of certain putative neurotransmitters in brain.
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References
Black, I. B. Increased tyrosine hydroxylase activity in frontal cortex and cerebellum after reserpine. Brain Res.95, 170–177 (1975).
Chase, T. N., Katz, R. I., Kopin, I. J. Effect of diazepam on fate of intracisternally injected serotonin14C. Neuropharmacology9, 103–108 (1970).
Cote, M. G., Blovin, A., Gascon, A. Influence of pretreatment with phenobarbitone on the ultrastructure of adrenergic nerve endings in guineapig seminal vesicles. J. Pharm. Pharmacol.22, 129–130 (1970).
Curtis, D. R., Johnston, G. A. R. Amino acid transmitters in mammalian central nervous system. Rev. Physiol. Biochem. Exp. Pharmacol.69, 97–188 (1974).
Curzon, G., Green, A. R. Rapid method for the determination of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in small regions of rat brain. Brit. J. Pharmacol.39, 653–655 (1970).
deMolina, A. F., Hunsperger, R. W. Organization of the subcortical system governing defence and flight reactions in the cat. J. Physiol. (London)160, 200–213 (1962).
Fennessy, M. R., Lee, J. R. The effect of benzodiazepines on brain amines of the mouse. Arch. Int. Pharmacodyn.197, 37–44 (1972).
Gershon, S., Baldessarini, R. J., Weeler, S. C. Biochemical effects of di-hydroxylated tryptamines on central indoleamine neurons. Neuropharmacology13, 987–1004 (1974).
Glowinski, J., Iversen, L. L. Regional studies of catecholamines in the rat brain. The disposition of (3H) norepinephrine, (3H) dopamine and (3H) DOPA in various regions of the brain. J. Neurochem.13, 655–669 (1966).
Heise, G. A., Boff, E. Taming action of chlordiazepoxide. Fed. Proc.20, 393 (1961).
Hrdina, P. D., Ghosh, P. K., Rastogi, R. B., Singhal, R. L. Ontogenic pattern of dopamine, acetylcholine and acetylcholinesterase in the brains of normal and hypothyroid rats. Can. J. Physiol. Pharmacol.53, 709 to 715 (1975).
Jenner, P., Chadwick, D., Reynolds, E. H., Marsden, C. D. Altered 5-HT metabolism with clonazepam, diazepam and diphenylhydantoin. J. Pharm. Pharmacol.27, 707–710 (1975).
Kilian, M., Frey, H. H. Central monoamines and convulsive thresholds in mice and rats. Neuropharmacology12, 681–692 (1973).
Lapierre, Y. D. Clinical and physiological assessment of chlorazepate, diazepam and placebo in anxious neurotics. Int. J. Clin. Pharmacol. Biopharm.11, 315–322 (1975).
McCaman, R. E. Microdetermination of catechol-O-methyl transferase in brain. Life Sci.4, 2353–2359 (1965).
McGeer, E. G., Gibson, S., McGeer, P. L. Some characteristics of brain tyrosine hydroxylase. Can. J. Biochem.45, 1557–1563 (1967).
Maickel, R. P., Cox, R. H., jr., Saillant, J., Miller, F. P. A method for the determination of serotonin and norepinephrine in discrete areas of rat brain. Int. J. Neuropharmacol.7, 275–281 (1968).
Meek, J. L. Fluorometric estimation of 4-hydroxy-3-methoxyphenyl-ethyleneglycol sulphate in brain. Brit. J. Pharmacol.45, 435–441 (1972).
Murphy, G. F., Robinson, D., Sharman, D. F. The effect of tropolone on the formation of 3,4-dihydroxyphenylacetic acid and 4-hydroxy-3-methoxyphenylacetic acid in the brain of the mouse. Brit. J. Pharmacol.36, 107–115 (1969).
Olds, J., Olds, M. E. Approach avoidance analysis of rat diencephalon. J. Comp. Neurol.120, 259–295 (1963).
Padjen, A., Bloom, F. Problems in the electrophysiological analysis of the site of action of benzodiazepines. In: Mechanisms of Action of Benzodiazepines (Costa, E., Green, P., eds.), pp. 93–103. New York: Raven Press. 1975.
Pfenninger, K., Akert, K., Moore, H., Sandri, C. The fine structure of presynaptic membranes. J. Ultrastructural Res.35, 451–459 (1971).
Randrup, A., Munkvad, I. Behavioural stereotypes induced by pharmacological agents. Pharmacopsychiatric and Neuropsychopharmacology1, 18–26 (1968).
Rastogi, R. B., Agarwal, R. A., Lapierre, Y. D., Singhal, R. L. Effects of acute diazepam and clobazam on spontaneous locomotor activity and central amine metabolism in rats. Europ. J. Pharmacol.43, 91–98 (1977).
Rastogi, R. B., Singhal, R. L. Influence of neonatal and adult hyperthyroidism on behaviour and biosynthetic capacity for norepinephrine, dopamine and 5-hydroxytryptamine in rat brain. J. Pharmacol. Exp. Ther.198, 609–618 (1976).
Reis, D. J., Fuxe, K. Brain norepinephrine: evidence that neuronal release is essential for sham rage behaviour following brain stem transaction in cat. Proc. Natl. Acad. Sci. (Wash.)64, 108–112 (1969).
Rickels, K., Pereira-Ogan, J. A., Chung, H. R., Gordon, P. E., Landis, W. B. Bromazepam and phenobarbital in anxiety: a controlled study. Curr. Therap. Res.15, 679–690 (1973).
Schildkraut, J. J., Kety, S. Biogenic amines and emotions. Science156, 21–30 (1967).
Spano, P. F., Neff, N. H. Procedure for simultaneous determination of dopamine, 3-methoxy-4-hydroxyphenylacetic acid and 3,4-hydroxy-phenylacetic acid in brain. Anal. Biochem.42, 113–118 (1971).
Stein, L., Wise, C. D., Belluzzi, J. D. Effects of benzodiazepines on central serotonergic mechanisms. In: Mechanism of Action of Benzodiazepines (Costa, E., Greengard, P., eds.), pp. 29–44. New York: Raven Press. 1975.
Suria, A., Costa, E. Action of diazepam, dibutyryl cGMP and GABA on presynaptic nerve terminals in bullfrog sympathetic ganglia. Brain Res.87, 102–106 (1975).
Takahashi, R., Aprison, M. H. Acetylcholine content of discrete areas of the brain obtained by a near freezing method. J. Neurochem.11, 887 to 898 (1964).
Whittaker, V. P. Catecholamine storage particles in the central nervous system. Pharmacol. Rev.18, 401–412 (1966).
Wise, C. D., Berger, B. D., Stein, L. Benzodiazepines: anxiety-reducing activity by reduction of serotonin turnover in the brain. Science177, 180–183 (1972).
Wurtman, R. J., Axelrod, J. A sensitive and specific assay for the estimation of monoamine oxidase. Biochem. Pharmacol.12, 1439–1440 (1963).
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Rastogi, R.B., Lapierre, Y.D. & Singhal, R.L. Effect of a new benzodiazepine bromazepam on locomotor performance and brain monoamine metabolism. J. Neural Transmission 42, 251–261 (1978). https://doi.org/10.1007/BF01673550
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DOI: https://doi.org/10.1007/BF01673550