Summary
A significant decrease in the number of 3H-quinuclidinyl benzilate (3H-QNB) binding sites in striatal membranes was observed in rats exposed to gamma-butyrolactone (GBL) during 3 weeks. This decrease in 3H-QNB binding was not due to a direct effect of GBL on muscarine receptors since no alterations of binding were produced by high concentrations of GBL or of its active metabolite gamma-hydroxybutyric acid (GHB) when added in vitro.
Challenge doses of pilocarpine were less effective in producing catalepsy and tremors in rats chronically treated with GBL. It is proposed that the partial inhibition of the nigro-striatal dopaminergic pathway produced by chronic GBL treatment leads to a persistent activation of the intrastriatal cholinergic interneurons, which are tonically inhibited by dopaminergic nigrostriatal neurons. The activation of striatal cholinergic interneurons results in a decreased number of muscarine receptors and in a lower sensitivity to cholinominetic agents.
Moreover, tolerance to the anesthetic effect of GBL was found to occur after chronic treatment with this drug. The brain levels of GHB at the time of regaining of the righting reflex were 50% higher in GBL pretreated animals then in controls. Indicating the tolerance to GBL-induced “sleep” is due to a decreased sensitivity of the effector to GHB rather than to a faster inactivation or elimination of the drug.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bartholini G (1980) Interaction of striatal dopaminergic, cholinergic and GABA-ergic neurons: relation to extrapyramidal function. Trends Pharmacol Sci 1:138–140
Bito LZ, Dawson MJ (1970) The site and mechanism of the control of cholinergic sensitivity. J Pharmacol Exp Ther 175:673–684
De Montis GM, Olianas MC, Serra G, Tagliamonte A, Scheel-Krüger J (1979) Evidence that a nigral gabaergic-cholinergic balance controls posture. Eur J Pharmacol 53:181–190
Ehlert FJ, Lloyd KG, Gadea-Ciria M (1973) Altered 3H quinuclidinyl benzilate binding in the striatum of rats following chronic cholinesterase inhibition with diisopropylfluoro phosphate. Mol Pharmacol 17:24–30
Ellman GL, Courtney KD, Andres V, Featherstone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95
Gessa GL, Vargiu L, Crabai F, Beoro GC Caboni F, Camba R (1966) Selective increase of brain dopamine induced by γ-hydroxybutyrate. Life Sci 5:1921–1930
Graham D, Madden J, Mitchelson F (1963) Changes in the sensitivity to cholinomimetic drugs of smooth and cardiac muscle in the rat induced by subacute administration of di-isopropyl phosphofluoridate. Eur J Pharmacol 28:27–36
Guidotti A, Ballotti PL (1970) Relationship between pharmacological effects and blood and brain levels of gamma-butyrolactone and gamma-hydroxybutyrate. Biochem Pharmacol 19:883–894
Hertting G, Zumstein A, Jackisch R, Hoffmann I, Starke K (1980) Modulation by endogenous dopamine of the release of acetylcholine in the caudate nucleus of the rabbit. Naunyn-Schmiedeberg's Arch Pharmacol 315:111–117
Jope RS (1979) High affinity choline transport and acetyl CoA production in brain and their roles in the regulation of acetylcholine synthesis. Brain Res Rev 1:313–344
Kato G, Carson S, Kemel ML, Glowinski J, Giorguieff MF (1978) Changes in striatal specific 3H-atropine binding after unilateral 6-hydroxydopamine lesions of nigrostriatal dopaminergic neurons. Life Sci 22:1607–1614
Lowry OH, Rosebrough NJ, Farr Al, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275
Matthews RT, Chiou CY (1978) Cholinergic stimulation of the caudate nucleus in rats: a model of Parkinson's disease. Neuropharmacology 17:879–882
Matthews RT, Chiou CY (1979) Effects of acute and chronic injections of carbachol in the rat caudate nucleus. Neuropharmacology 18:291–294
McCaman RE, Hunt JM (1965) Microdetermination of choline acetylase in nervous tissue. J Neurochem 12:253–259
Murrin LC, Roth RH (1976) Dopaminergic neurons: reversal of effects elicited by γ-butyrolactone by stimulation of the nigro-neostriatal pathway. Naunyn-Schmiedeberg's Arch Pharmacol 295:15–20
Nomura Y, Kajiyama H, Nakata Y, Segawa T (1979) Muscarinic cholinergic binding in striatal and mesolimbic areas of the rat: reduction by 6-hydroxydopa. Eur J Pharmacol 58:125–131
Nowycky MC, Roth RH (1979) Chronic gamma-butyrolactone (GBL) treatment; a potential model of dopamine hypoactivity. Naunyn-Schmiedeberg's Arch Pharmacol 309:247–254
Potemska A, Gradkowska M, Oderfeld-Nowak B (1975) Early changes in acetylcholine pools in the hippocampus of the rat brain after septal lesions. J Neurochem 24:787–789
Roth RH, Suhr Y (1970) Mechanism of γ-hydroxybutyrate-induced increase in brain dopamine and its relationship to “sleep”. Biochem Pharmacol 19:3001–3012
Roth RH, Walters JR, Aghajanian GK (1973) Effect of impulse Flow on the release and synthesis of dopamine in the rat striatum. In: Usdin E, Snyder SH (eds) Frontiers in catecholamine research. Pergamon Press, New York, pp 567–574
Roth RH, Murrin LC, Walters JR (1976) Central dopaminergic neurons: effects of alterations in impulse flow on the accumulation of dihydroxyphenylacetic acid. Eur J Pharmacol 36:163–171
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 295:9–14
Simon JR, Atweh S, Kuhar MJ (1976) Sodium-dependent high affinity choline uptake: a regulatory step in the synthesis of acetylcholine. J Neurochem 26:909–922
Snedecor GW, Cochran WG (1967) Statistical methods. The Iowa State University Press, Ames, Iowa, USA
Spano PF, Tagliamonte A, Tagliamonte P, Gessa GL (1971) Stimulation of brain dopamine synthesis by γ-hydroxybutyrate. J Neurochem 18:1831–1836
Stadler H, Lloyd KG, Gadea-Ciria M (1973) Enhanced striatal acetylcholine release by chlorpromazine and its reversal by apomorphine. Brain Res 55:476–480
Stock G, Magnusson T, Andén N-E (1973) Increase in brain dopamine after axotomy or treatment with gamma hydroxybutyric acid due to elimination of the nerve impulse flow. Naunyn-Schmiedeberg's Arch Pharmacol 278:347–361
Walters JR, Roth RH (1972) Effect of Gamma-hydroxybutyrate on dopamine and dopamine metabolites in the rat striatum. Biochem Pharmacol 21:2111–2121
Yamamura HI, Snyder SH (1974) Muscarinic cholinergic binding in rat brain. Proc Natl Acad Sci USA 71:1725–1729
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Giorgi, O., Rubio, M.C. Decreased 3H-l-quinuclidinyl benzilate binding and muscarine receptor subsensitivity after chronic gamma-butyrolactone treatment. Naunyn-Schmiedeberg's Arch. Pharmacol. 318, 14–18 (1981). https://doi.org/10.1007/BF00503306
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00503306