Summary
Several benzodiazepines (chlordiazepoxide, clonazepam, diazepam and flunitrazepam) markedly counteracted the elevation of the homovanillic acid (HVA) content of the rat brain induced by neuroleptics (haloperidol, pimozide, chlorpromazine, and clozapine). A similar effect was obtained with the inhibitor of GABA transaminase, aminooxyacetic acid (AOAA). The interaction of benzodiazepines with the neuroleptic-induced HVA increase was similar in the striatum and in the limbic forebrain, and was antagonized by the GABA receptor-blocking agent, picrotoxin. Both the benzodiazepines used and AOAA potentiated the cataleptic effect of the four neuroleptics.
It is concluded that benzodiazepines, by intensifying GABA-ergic transmission, enhance the ongoing inhibition of mesencephalic dopamine neurons exerted by the striatonigral GABA system. As a consequence, the feedback activation of dopamine neurons induced by the neuroleptic blockade of dopamine receptors in the striatum and the limbic system is attenuated. This results in a reduction of the neuroleptic-induced increase of HVA and in the potentiation of the cataleptic effect of neuroleptics.
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References
Anagnoste, B., Shirron, C., Friedman, E., Goldstein, M.: Effect of dibutyryl cyclic adenosine monophosphate on14C-dopamine biosynthesis in rat brain striatal slices. J. Pharmacol. exp. Ther.191, 370–376 (1974)
Andén, N.-E.: Inhibition of the turnover of the brain dopamine after treatment with the gammaaminobutyrate: 2-oxyglutarate transaminase inhibitor aminooxyacetic acid. Naunyn-Schmiedeberg's Arch. Pharmacol.283, 419–424 (1974)
Andén, N.-E., Roos, B.-E., Werdinius, B.: On the occurrence of homovanillic acid in brain and cerebrospinal fluid and its determination by a fluorometric method. Life Sci.2, 448–458 (1963)
Anton, A. H., Sayre, D. F.: A study of the factors affecting the aluminium oxide trihydroxyindol procedure for the analysis of catecholamines. J. Pharmacol. exp. Ther.138, 360–375 (1962)
Bartholini, G., Haefely, W., Jalfre, M., Keller, H. H., Pletscher, A.: Effects of clozapine on cerebral catecholaminergic neuron systems. Brit. J. Pharmacol.46, 736–740 (1972)
Bartholini, G., Keller, H. H., Pieri, L., Pletscher, A.: The effect of diazepam on the turnover of cerebral dopamine. In: The Benzodiazepines (S. Garattini, E. Mussini, and L. O. Randall, eds.), p. 235–240. New York: Raven Press 1973)
Bartholini, G., Keller, H. H., Pletscher, A.: Drug-induced changes of dopamine turnover in striatum and limbic system of the rat. J. Pharm. Pharmacol.27, 439–442 (1975)
Boissier, J.-R., Simon, P.: Un test simple pour l'étude quantitative de la catatonie provoquée chez le rat par les neuroleptiques. Application à l'étude des anticatatoniques. Thérapie18, 1257–1277 (1963)
Bunney, B. S., Aghajanian, G. K.: Evidence for drug actions on both pre- and postsynaptic catecholamine receptors in the CNS. In: Pre- and postsynaptic receptors (E. Usdin and W. E. Bunney, Jr., eds.), pp. 89–122. New York: Marcel Dekker Inc. 1975
Bunney, B. S., Walters, J. R., Roth, R. H., Aghajanian, G. K.: Dopaminergic neurons: effect of antipsychotic drugs and amphetamine on single cell activity. J. Pharmacol. exp. Ther.185, 560–571 (1973)
Carlsson, A.: Receptor-mediated control of dopamine metabolism. In: Pre- and postsynaptic receptors (E. Usdin and W. E. Bunney, Jr., eds.), pp. 49–65. New York: Marcel Dekker Inc. 1975
Carlsson, A., Persson, T., Roos, B.-E., Wålinder, J.: Potentiation of phenothiazines by α-methyltyrosine in treatment of chronic schizophrenia. J. Neural Trans.33, 83–90 (1972)
Christiansen, J., Squires, R. F.: Antagonistic effects of apomorphine and haloperidol on rat striatal synaptosomal tyrosine hydroxylase. j. Pharm. Pharmacol.26, 367–369 (1974)
Costa, E., Guidotti, A., Mao, C. C., Suria, A.: New concepts on the mechanism of action of benzodiazepines. Life Sci.17, 167–186 (1975)
Costall, B., Naylor, R. J.: The importance of the ascending dopaminergic systems to the extrapyramidal and mesolimbic brain areas for the cataleptic action of the neuroleptic and cholinergic agents. Neuropharmacology13, 353–364 (1974)
Da Prada, M., Pletscher, A.: on the mechanism of chlorpromazine-induced changes of cerebral homovanillic acid levels. J. Pharm. Pharmacol.18, 628–630 (1966)
Farnebo, L.-O., Hamberger, B.: Catecholamine release and receptors in brain slices. In: Frontiers in Catecholamine Research (E. Usdin and S. H. Snyder, eds.), pp. 589–593. New York: Pergamon Press 1973
Feltz, P.: γ-Aminobutyric acid and a caudato-nigral inhibition. Canad. J. Physiol. Pharmacol.49, 1113–1115 (1971)
Fonnum, F., Grofová, I., Rinvik, E., Storm-Mathisen, J., Walberg, F.: Origin and distribution of glutamate decarboxylase in substantia nigra of the cat. Brain Res.71, 77–92 (1974)
Haefely, W., Kulcsár, A., Möhler, H., Pieri, L., Polc, P., Schaffner R.: Possible involvement of GABA in the central actions of benzodiazepines. In: Mechanism of action of Benzodiazepines (E. Costa and P. Greengard, eds.), pp. 131–151. New York: Raven Press 1975)
Hattori, T., McGeer, P. L., Fibiger, H. C., McGeer, E. G.: On the source of Gaba-containing terminals in the substantia nigra. Electron microscopic autoradiographic and biochemical studies. Brain Res.54, 103–114 (1973)
Iversen, L. L.: The uptake, storage, release and metabolism of GABA in inhibitory nerves. In: Perspectives in Neuropharmacology (S. Snyder, ed.), pp. 75–110. New York: Oxford University Press 1972
Jalfre, M., Haefely, W.: Effects of some centrally acting agents in rats after intraventricular injections of 6-hydroxydopamine. In: 6-Hydroxydopamine and catecholamine neurons (T. Malmfors and H. Thoenen, eds.), pp. 333–346. Amsterdam: North-Holland Publ. Comp. 1971
Kim, J. S., Bak, I. J., Hassler, R., Okada, Y.: Role of γ-aminobutyric acid (GABA) in the extrapyramidal motor system. 2. Some evidence for the existence of a type of GABA-rich strio-nigral neurons. Exp. Brain Res.14, 95–104 (1971)
Lahti, R. A., Losey, E. G.: Antagonism of the effects of chlorpromazine and morphine on dopamine metabolism by GABA. Res. Comm. chem. Path. Pharmacol.7, 31–40 (1974)
Laverty, R., Taylor, K. M.: The fluorometric assay of catecholamines and related compounds: improvements and extensions to the hydroxyindole technique. Analyt. Biochem.22, 269–279 (1968)
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)
Polc, P., Haefely, W.: The effect of diazepam on inhibition in the cuneate nucleus of decerebrate cats. Experientia (Basel)31, 731 (1975)
Polc, P., Haefely, W.: Effects of two benzodiazepines, phenobarbitone, and baclofen on synaptic transmission in the cat cuneate nucleus. Naunyn-Schmiedeberg's Arch. Pharmacol. (in press, 1976)
Polc, P., Möhler, H., Haefely, W.: The effect, of diazepam on spinal cord activities: possible sites and mechanism of action. Naunyn-Schmiedeberg's Arch. Pharmacol.284, 319–337 (1974)
Schaffner, R., Haefely, W.: The effect of diazepam and bicuculline on the strio-nigral evoked potential. Experientia (Basel)31, 732 (1975)
Shore, P. A., Dorris, R. L.: On a prime role of newly synthesized dopamine in striatal function. Europ. J. Pharmacol.30, 315–318 (1975)
Westerink, B. H. C., Korf, J.: Determination of nanogram amounts of homovanillic acid in the central nervous system with a rapid semiautomated fluorometric method. Biochem. Med.12, 106–115 (1975a)
Westerink, B. H. C., Korf, J.: Influence of drugs on striatal and limbic homovanillic acid concentration in the rat brain. Europ. J. Pharmacol.33, 31–40 (1975b)
Yoshida, M., Precht, W.: Monosynaptic inhibition of neurons of the substantia nigra by caudato-nigral fibers. Brain Res.32, 225–228 (1971)
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Keller, H.H., Schaffner, R. & Haefely, W. Interaction of benzodiazepines with neuroleptics at central dopamine neurons. Naunyn-Schmiedeberg's Arch. Pharmacol. 294, 1–7 (1976). https://doi.org/10.1007/BF00692778
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DOI: https://doi.org/10.1007/BF00692778