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Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 322, Issue 1, pp 42–48 | Cite as

Mode of action of gamma-butyrolactone on the central cholinergic system

  • Herbert Ladinsky
  • Silvana Consolo
  • Alberto Zatta
  • Annamaria Vezzani
Article

Summary

Gamma-butylactone (GBL), a drug depressing the central nervous system, produced marked increases in acetylcholine contents in rat brain hemispheric regions (striatum, hippocampus, cortex) and in strital choline content without modifying choline acetyltransferase or acetylcholinesterase activities.

In the hippocampus GBL also strongly decreased the acetylcholine turnover rate and inhibited the high affinity uptake of choline. Its increase in acetylcholine content was prevented by an acute electrolytic lesion of the medial septum but not by a wide array of drug treatments designed to interfere with neurotransmission in various pathways. The results are taken to indicate that GBL directly depresses the cholinergic septal-hippocampal afferents by interrupting impulse flow.

In the striatum, too, GBL markedly depressed the acetylcholine synthesis rate but had no effect on the high affinity choline uptake process. Such dissociation of the two phenomena had previously been observed using other drugs and may denote that acetylcholine synthesis in this region is regulated differently from that in the hippocampus.

By comparison, gamma-hydroxybutyric acid (GHBA), an active metabolite which shares with GBL the capacity to produce a somnolent state and depress impulse flow in the dopaminergic nigroneostriatal pathway, had no effect on either striatal acetylcholine content or on hippocampal high affinity choline uptake. The results suggest that GBL can be distinguished from GHBA in its neuropharmacological central cholinergic effects.

Key words

Gamma-butyrolactone Gamma-hydroxybutyric acid Acetylcholine Choline uptake Brain Sleep 

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References

  1. Andén N-E (1974) Inhibition of the turnover of the brain dopamine after treatment with the gammaaminobutyrate: 2-Oxyglutarate transaminase inhibitor aminooxyacetic acid. Naunyn-Schmiedeberg's Arch Pharmacol 283:419–424Google Scholar
  2. Andén N-E, Stock G (1973) Inhibitory effect of gammahydroxybutyric acid and gammaainobutyric acid on the dopamine cells in the substantia nigra. Naunyn-Schmiedeberg's Arch Pharmacol 279:89–92Google Scholar
  3. Antonelli T, Beani L, Bianchi C, Pedata F, Pepeu G (1981) Changes in synaptosomal high affinity choline uptake following electrical stimulation of guinea-pig cortical slices: Effect of atropine and physostigmine. Br J Pharmacol 74:525–531Google Scholar
  4. Atweh SF, Kuhar MJ (1976) Effects of anesthetics and septal lesions and stimulation on3H-acetylcholine formation in rat hippocampus. Eur J Pharmacol 37:311–319Google Scholar
  5. Atweh S, Simon JR, Kuhar MJ (1975) Utilization of sodium-dependent high affinity choline uptake in vitro as a measure of the activity of cholinergic neurons in vivo. Life Sci 17:1535–1544Google Scholar
  6. Benavides J, Rumigny JF, Bourguignon JJ, Cash C, Wermuth CG, Mandel P, Vincendon G, Maitre M (1982) High affinity binding site for γ-hydroxybutyric acid in rat brain. Life Sci 30:953–961Google Scholar
  7. Bessman SP, Fishbein WN (1963) Gamma-hydroxybutyrate, a normal brain metabolite, Nature 200:1207–1208Google Scholar
  8. Chéramy A, Nieoullon A, Glowinski J (1978) In vivo changes in dopamine release in cat caudate nucleus and substantia nigra induced by nigral application a various drugs including GABAergic agonists and antagonists. In: Garattini S, Pujol JF, Samanin R (eds) Interactions between putative neurotransmitters in the brain. Raven Press, New York, pp 175–190Google Scholar
  9. Collier B, Katz HS (1974) Acetylcholine synthesis from recaptured choline by a sympathetic ganglion. J Physiol (London) 238:639–655Google Scholar
  10. Consolo S, Ladinsky H, Bianchi S (1975) Decrease in rat striatal acetylcholine levels by some direct- and indirect-acting dopaminergic antagonist. Eur J Pharmacol 33:345–351Google Scholar
  11. Consolo S, Ladinsky H, Pugnetti P, Fusi R, Crunelli V (1981) Increase in rat striatai acetylcholine content by bromocriptine: Evidence for an indirect dopaminergic action. Life Sci 29:457–465Google Scholar
  12. DeFeudis FV, Collier B (1970) Amino acids of brain and γ-hydroxybutyrate-induced depression. Arch Int Pharmacodyn 187:30–36Google Scholar
  13. Di Giulio AM, Groppetti A, Cattabeni F, Galli CL, Maggi A, Algeri S, Ponzio F (1978) Significance of dopamine metabolites in the evaluation of drugs acting on dopaminergic neurons. Eur J Pharmacol 52:201–207Google Scholar
  14. Giarman NJ, Roth RH (1964) Differential estimation of gammabutyrolactone and gamma-hydroxybutyric acid in rat blood and brain. Science 145:583–584Google Scholar
  15. Giorgi O, Rubio MC (1981) Decreased3H-L-quinuclidinyl benzilate binding and muscarine receptor subsensitivity after chronic gammabutyrolactone treatment. Naunyn-Schmiedeberg's Arch Pharmacol 318:14–18Google Scholar
  16. Guyenet PG, Agid Y, Javoy F, Beaujouan JC, Rossier J, Glowinski J (1975) Effects of dopaminergic receptor agonists and antagonists on the activity of the neo-striatal cholinergic system. Brain Res 84:227–244Google Scholar
  17. Jope RS (1979) High affinity choline transport and acetylCoA production in brain and their roles in the regulation of acetylcholine synthesis. Brain Res 180:313–344Google Scholar
  18. Ladinsky H, Consolo S, Bareggi SR (1972) A simple method for detecting overlap of naogram quantities of choline onto the acetylcholine band in paper electrophoresis. Anal Biochem 50:460–466Google Scholar
  19. Ladinsky H, Consolo S, Bianchi S, Samanin R, Ghezzi D (1975) Cholinergic-dopaminergic interaction in the striatum: The effect of 6-hydroxydopamine or pimozide treatment on the increased striatal acetylcholine levels induced by apomorphine, piribedil andd-amphetamine. Brain Res 84:221–226Google Scholar
  20. Ladinsky H, Consolo S, Bianchi S, Jori A (1976) Increase in striatal acetylcholine by picrotoxin in the rat: Evidence for a gabergicdopaminergic-cholinergic link. Brain Res 108:351–361Google Scholar
  21. Ladinsky H, Consolo S, Forloni G, Tirelli AS (1981) Studies on the indirect feedback inhibition of cholinergic neurons triggered by oxotremorine in striatum. Brain Res 225:217–223Google Scholar
  22. McCaman MW, Tomey LR, McCaman RE (1968) Radiomimetric assay of acetylcholinesterase activity in submicrogram amounts of tissue. Life Sci 7:233–244Google Scholar
  23. McCaman RE, Hunt JM (1965) Microdetermination of choline acetylase in nervous tissue. J Neurochem 12:253–259Google Scholar
  24. McGeer PL, Grewaal DS, McGeer EG (1974) Influence of noncholinergic drugs on rat striatal acetylcholine levels. Brain Res 80:211–217Google Scholar
  25. Menon MK, Fleming RM, Clark WG (1974) Studies on the biochemical mechanisms of the central effects of gamma-hydroxybutyric acid. Biochem Pharmacol 23:879–885Google Scholar
  26. Mitoma Ch, Neubauer SE (1968) Gamma-hydroxybutyric acid and sleep. Experientia 24:12–13Google Scholar
  27. Mulder AH, Yamamura HI, Kuhar MJ, Snyder SH (1974) Release of acetylcholine from hippocampal slices by potassium depolarization: Dependence on high affinity choline uptake. Brain Res 70:372–376Google Scholar
  28. Racagni G, Cheney DL, Zsilla G, Costa E (1976) The measurement of acetylcholine turnover rate in brain structures. Neuropharmacology 15:723–736Google Scholar
  29. Rommelspacher H, Kuhar MJ (1975) Effects of dopaminergic drugs and acute medial forebrain bundle lesions on striatal acetylcholine levels. Life Sci 16:65–70Google Scholar
  30. Roth RH (1971) Effect of anesthetic doses of γ-hydroxybutyrate on subcortical concentrations of homovanillic acid. Eur J Pharmacol 15:52–59Google Scholar
  31. Roth RH, Giarman NJ (1970) Natural occurrence of gammahydroxybutyrate in mammalian brain. Biochem Pharmacol 19:1087–1093Google Scholar
  32. Roth RH, Suhr Y (1970) Mechanism of the γ-hydroxybutyrate-induced increase in brain dopamine and its relationship to “sleep”. Biochem Pharmacol 19:3001–3012Google Scholar
  33. Roth RH, Walters JR, Aghajanian GK (1974) Effects of impulse flow on the release and synthesis of dopamine in the rat striatum. Biochem Pharmacol 23:457–464Google Scholar
  34. Saelens JK, Allen MP, Simke JP (1970) Determination of acetylcholine and choline by an enzymatic assay. Arch Int Pharmacodyn 186:279–286Google Scholar
  35. Schwarcz R, Zaczek R, Coyle JT (1978) Microinjection of kainic acid into the rat hippocampus. Eur J Pharmacol 50:209–220Google Scholar
  36. Sethy VH, Kuhar MJ, Roth RH, Van Woert MH, Aghajanian GK (1973) Cholinergic neurons: Effect of acute spetal lesion on acetylcholine and choline content of rat hippocampus. Brain Res 55:481–484Google Scholar
  37. Sethy VH, Roth RH, Walters JR, Marini J, Van Woert MH (1976) Effect of anesthetic doses of γ-hydroxybutyrate on the acetylcholine content of rat brain. Naunyn-Schmiedeberg's Arch Pharmacol 295:9–14Google Scholar
  38. Sherman KA, Hanin I, Zigmond MJ (1978) The effect of neuroleptics on acetylcholine concentration and choline uptake in striatum: Implications for regulation of acetylcholine metabolism. J Pharmacol Exp Ther 206:677–686Google Scholar
  39. Snead OC III (1977) Gamma hydroxybutyrate. Life Sci 20:1935–1944Google Scholar
  40. Stock G, Magnusson T, Andén N-E (1973) Increase in brain dopamine after axotomy or treatment with gammahydroxybutyric acid due to elimination of the nerve impulse flow. Naunyn-Schmiedeberg's Arch Exp Pathol Pharmacol 278:347–361Google Scholar

Copyright information

© Springer-Verlag 1983

Authors and Affiliations

  • Herbert Ladinsky
    • 1
  • Silvana Consolo
    • 1
  • Alberto Zatta
    • 1
  • Annamaria Vezzani
    • 1
  1. 1.Istituto di Ricerche Farmacologiche “Mario Negri”MilanItaly

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