Bromocriptine, dihydroergotoxine, methysergide, d-LSD, CF 25-397, and 29-712: Effects on the metabolism of the biogenic amines in the brain of the rat
The effects of the ergolene derivatives bromocriptine, dihydroergotoxine, methysergide, d-LSD, CF 25-397, and 29-712 on the metabolism of the biogenic amines in the brain of the rat were investigated.
All six ergolene derivatives were found to increase the concentration of 4-hydroxy-3-methoxyphenylethylene glycol sulphate in the brain stem, i.e., to increase the turnover of noradrenaline (NA). Since in brain homogenates the agents inhibited the binding of 3H-dihydroergocryptine to α-adrenoceptors, but only weakly inhibited the binding of 3H-alprenolol to β-adrenoceptors, it is suggested that the increased turnover of NA may be a consequence of a blockade of α-adrenoceptors by ergolenes.
All of the ergolenes increased the concentration of serotonin (5-HT) in the cortex, but only bromocriptine and 29-712 increased the concentration of 5-hydroxyindoleacetic acid (5-HIAA), the other compounds decreasing the concentration of this metabolite, i.e., inhibiting 5-HT turnover. Reserpine-induced PGO waves in the cat were inhibited by all six compounds, bromocriptine and 29-712 being the least active. Both of these findings suggest that the ergolenes possess serotonergic activity. The increase in the concentration of 5-HIAA after bromocriptine and 29-712 may be secondary to some action on other systems.
The actions of the ergolenes on the metabolism of dopamine (DA) in the striatum are more complex. Bromocriptine, 29-712, and, to a much lesser extent, dihydroergotoxine reduced the concentration of 3,4-dihydroxyphenylacetic acid (DOPAC), i.e., they inhibited DA turnover. These findings are compatible with the proposed dopaminergic activity of the drugs. CF 25-397 caused a slight increase in the DOPAC concentration at high doses, and d-LSD and methysergide caused pronounced increases. At doses below 1 mg/kg i.p., d-LSD decreased the DOPAC concentration. This biphasic effect of d-LSD may be due to interaction with different types of DA receptors or may reflect some secondary action of the compound.
The profiles of activity of the various ergolenes are discussed. Bromocriptine and 29-712, wich have similar profiles of activity, can be clearly differentiated from the other ergolenes. CF 25-397 seems to be a potent and, at low doses, specific serotonergic drug.
Key wordsErgolenes Rat brain Dopamine Noradrenaline Serotonin PGO waves Cat
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- Aghajanian, G. K.: Influence of drugs on the firing of serotonincontaining neurons in brain. Fed. Proc. 31, 91–96 (1972)Google Scholar
- Andén, N.-E., Corrodi, H., Fuxe, K., Hökfelt, T.: Evidence for central 5-hydroxytryptamine receptor stimulation by lysergic acid diethylamide. Br. J. Pharmacol. 34, 1–7 (1968)Google Scholar
- Anton, A. H., Sayre, D. F.: A study of the factors affecting the aluminium oxide trihydroxyindole procedure for the analysis of catecholamines. J. Pharmacol. Exp. Ther. 138, 360–375 (1962)Google Scholar
- Burt, D. R., Creese, I., Snyder, S. H.: Binding interactions of lysergic acid diethylamide and related agents with dopamine receptors in the brain. Mol. Pharmacol. 12, 631–638 (1976)Google Scholar
- Bylund, D. B., Snyder, S. H.: Beta adrenergic receptor binding in membrane preparations from mammalian brain. Mol. Pharmacol. 12, 568–580 (1976)Google Scholar
- Calne, D. B., Kartzinel, R., Shoulson, I.: An ergot derivative in the treatment of Parkinson's disease. Postgrad. Med. J. 52, 81 (1976)Google Scholar
- Calne, D. B., Teychenne, P. F., Claveria, L. E., Eastman, R., Greenacre, J. K., Petrie, A.: Bromocriptine in parkinsonism, Br. Med. J. 1974 IV, 442–444Google Scholar
- Carlsson, A., Lindqvist, M., Fuxe, K., Hökfelt, T.: Histochemical and biochemical effects of diethyldithiocarbamate on tissue catecholamines. J. Pharm. Pharmacol. 18, 60–62 (1966)Google Scholar
- Corrodi, H., Fuxe, K., Hökfelt, T., Lidbrink, P., Ungerstedt, U.: Effect of ergot drugs on central catecholamine neurons: evidence for a stimulation of central dopamine neurons. J. Pharm. Pharmacol. 25, 409–412 (1973)Google Scholar
- Corrodi, H., Hanson, L. C. F.: Central effects of an inhibitor of tyrosine hydroxylation. Psychopharmacologia (Berl.) 10, 116–125 (1966)Google Scholar
- DaPrada, M., Saner, A., Burkard, W. P., Bartholini, G., Pletscher, A.: Lysergid acid diethylamide: evidence for stimulation of cerebral dopamine receptors. Brain Res. 94, 67–73 (1975)Google Scholar
- Freedman, D. X.: Effects of LSD-25 on brain serotonin. J. Pharmacol. Exp. Ther. 134, 160–166 (1961)Google Scholar
- Giacalone, E., Valzelli, L.: A spectroflurometric method for the simultaneous determination of 2-(5-hydroxyindol-3-yl)-ethylamine (serotonin) and 5-hydroxyindol-3-yl-acetic acid in the brain. Pharmacology 2, 171–175 (1969)Google Scholar
- Greenberg, D. A., U'Prichard, D. C., Snyder, S. H.: Alphanoradrenergic receptor binding in mammalian brain: differential labeling of agonist and antagonist states. Life Sci. 19, 69–76 (1976)Google Scholar
- Hökfelt, T., Fuxe, K.: Effects of prolactin and ergot alkaloids on the tubero-infundibular dopamine (DA) neurons. Neuroendocrinology 9, 100–122 (1972)Google Scholar
- Hungen, K. von, Roberts, S., Hill, D. F.: LSD as an agonist and antagonist at central dopamine receptors. Nature 252, 588–589 (1974)Google Scholar
- Jaton, A. L., Loew, D. M., Vigouret, J. M.: CF 25-397 (9,10-dihydro-6-methyl-8β-[2-pyridylthiomethyl]ergoline), a new central dopamine receptor agonist. Br. J. Pharmacol. 56, 371P (1975)Google Scholar
- Jouvet, M.: The role of monoamines and acetylcholine-containing neurons in the regulation of the sleep-waking cycle. Ergeb. Physiol. 64, 166–307 (1972)Google Scholar
- Laverty, R., Taylor, K. M.: The fluorometric assay of catecholamines and related compounds: Improvements and extensions to the hydroxyindole technique. Anal. Biochem. 22, 269–279 (1968)Google Scholar
- Lieberman, A., Kupersmith, M., Estey, E., Goldstein, M.: Treatment of parkinson's disease with bromocriptine. New Engl. J. Med. 295, 1400–1404 (1976)Google Scholar
- Loew, D. M., Vigouret, J. M., Jaton, A. L.: Neuropharmacological investigations with two ergot alkaloids, hydergine and bromocriptine. Postgrad. Med. J. [Suppl.] 52, 40–46 (1976)Google Scholar
- Meek, J. L., Neff, N. H.: Fluorometric estimation of 4-hydroxy-3-methoxyphenyl-ethyleneglycol sulphate in brain. Br. J. Pharmacol. 45, 435–441 (1972)Google Scholar
- Pieri, L., Pieri, M., Haefely, W.: LSD as an agonist of dopamine receptors in the striatum. Nature 252, 586–588 (1974)Google Scholar
- Spano, P. F., Neff, N. H.: Procedure for the simultaneous determination of dopamine, 3-methyoxy-4-hydroxyphenylacetic acid, and 3,4-dihydroxyphenyl-acetic acid in brain. Anal. Biochem. 42, 113–118 (1971)Google Scholar
- Tagliamonte, A., Biggio, G., Vargiu, L., Gessa, G. L.: Increase of brain tryptophan and stimulation of serotonin synthesis by salicylate. J. Neurochem. 20, 909–912 (1973)Google Scholar
- Tagliamonte, A., Tagliamonte, P., Perez-Cruet, J., Gessa, G. L.: Increase of brain tryptophan caused by drugs which stimulate serotonin synthesis. Nature (New Biol.) 229, 125–126 (1971)Google Scholar
- Vigouret, J. M., Bürki, H. R., Jaton, A. L., Züger, P. E., Loew, D. M.: Neurochemical and neuropharmacological investigations with four ergot derivatives: bromocriptine, dihydroergotoxine, CF 25-397 and 29-712. Pharmacology 16, Suppl. 1, 156–173 (1978)Google Scholar
- Waldmeier, P., Maitre, L.: An automated fluorometric method for the estimation of dopamine in brain tissue extracts. Anal. Biochem. 51, 474–481 (1973)Google Scholar
- Weil-Malherbe, H.: The chemical estimation of catecholamines and their metabolites in body fluids and tissue extracts. In: Methods of biochemical analysis, suppl. vol., D. Glick, ed., pp. 123–126. New York, London, Sydney, Toronto: Interscience 1971Google Scholar
- Williams, L. T., Mullikin, D., Lefkowitz, R. J.: Identification of α-adrenergic receptors in uterine smooth muscle membranes by 3H-dihydroergocryptine binding. J. Biol. Chem. 251, 6915–6923 (1976)Google Scholar
- Zuspan, F. P., Cooley, M. A.: Semi-automated fluorometric trihydroxyindole method for determining epinephrine (E) and norepinephrine (NE). In: Advances in automated analysis, vol. I, pp. 351–354. Technicon Int. Congress 1969Google Scholar