Summary
Gamma-butyrolactone (GBL) is a general depressant of the central nervous system which has proved to be a useful tool for studying the dopamine system. Administration of GBL to rats produces an acute blockade of impulse flow in the nigro-neostriatal dopaminergic pathway, in effect causing a reversible pharmacological lesion of this pathway. In this study the effects of chronic treatment of rats with GBL were examined. After 1 month of chronic treatment, the average firing rates of A9 dopamine cells were significantly depressed below those of control rats. Striatal dihtdroxyphenylacetic acid levels were also depressed, while striatal dopamine levels and in vivo tyrosine hydroxylase activity (measured by dopa accumulation after inhibition of dopa decarboxylase) were at control values.
Tolerance developed to the behavioral effects of GBL (measured by duration of loss of righting reflex after a challenge dose). The tolerance was partially overcome by increasing the amount of the challenge dose. Tolerance also developed to the ability of a challenge dose to elicit increased dopamine synthesis. However, synthesis responded normally to mechanical lesion and electrical stimulation of the dopamine fibers. Both post-and presynaptic dopamine receptors became supersensitive after chronic treatment with GBL.
These findings suggest that chronic treatment with GBL may provide a model system for studying the effects of partial deprivation of dopaminergic activity.
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References
Aghajanian, G. K., Roth, R. H.: γ-Hydroxybutyrate-induced increase in brain dopamine: Localization by fluorescence microscopy. J. Pharmacol. Exp. Ther. 175, 131–138 (1970)
Basil, B., Blair, A. M. J. W., Holmes, S. W.: The action of sodium-4-hydroxybutyrate on spinal reflexes. Br. J. Pharmacol. 22, 318–328 (1964)
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)
Gessa, G. L., Vargiu, L, Crabai, F., Boero, G. C., Caboni, F., Camba, R.: Selective increase of brain dopamine induced by γ-hydroxybutyrate. Life Sci. 5, 1921–1930 (1966)
Gianutsos, G., Hynes, M. D., Lal, H.: Enhancement of apomorphine-induced inhibition of striatal dopamine-turnover following chronic haloperidol. Biochem. Pharmacol. 24, 581–582 (1975)
Gianutsos, G., Moore, K. E.: Tolerance to the effects of baclofen and butyrolactone on locomotor activity and dopaminergic neurons in the mouse. J. Pharmacol. Exp. Ther. 207, 859–869 (1978)
Gianutsos, G., Thronburg, J. E., Moore, K. E.: Differential actions of dopamine agonists and antagonists on the γ-butyrolactone-induced increase in mouse brain dopamine. Psychopharmacology 50, 225–229 (1976)
Giarman, N. J.: Antibiotic lactones and synthetic analogs: The relation of chemical structures to chemotherapeutic and pharmacodynamic properties. Ph. D. Thesis. Yale University (1948)
Iversen, S. D., Creese, I.: Behavioral correlates of dopaminergic supersensitivity. Adv. Neurol. 9, 81–92 (1975)
Kehr, W., Carlsson, A., Lindquist, M.: A method for the determination of 3,4-dihydroxyphenylalanine (DOPA) in brain. Naunyn-Schmiedeberg's Arch. Pharmacol. 274, 273–280 (1972)
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)
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. Br. J. Pharmacol. 36, 107–115 (1969)
Murrin, L. C., Roth, R. H.: Dopaminergic neurons: Effects of electrical stimulation on tyrosine hydroxylase. Mol. Pharmacol. 12, 1070–1081 (1976)
Nowycky, M. C., Roth, R. H.: Supersensitivity of presynaptic dopamine receptors following chronic treatment with fluphenazine. Trans. Am. Neurochem. Soc. 7, 232 (1976)
Nowycky, M. C., Roth, R. H.: Presynaptic dopamine receptors: development of supersensitivity following treatment with fluphenazine decanoate. Naunyn-Schmiedeberg's Arch. Pharmacol. 300, 247–254 (1977)
Nowycky, M. C., Roth, R. H.: Dopaminergic neurons: Role of presynaptic receptors in the regulation of transmitter biosynthesis. Prog. Neuro-Psychopharmacol. 2, 139–158 (1978)
Nowycky, M. C., Walters, J. R., Roth, R. H.: Dopaminergic neurons: Effects of acute and chronic morphine administration on single cell activity and transmitter metabolism. J. Neural Transm. 42, 99–116 (1978)
Roth, R. H., Suhr, Y.: Mechanism of γ-hydroxybutyrate-induced increase in brain dopamine and its relationship to “sleep”. Biochem. Pharmacol. 19, 3001–3012 (1970)
Roth, R. H., Murrin, L. C., Walters, J. R.: Central dopaminergic neurons: effects of alterations in impulse flow on the accumulation of dihydroxyphenylacetic acid. Eur. J. Pharmacol. 36, 163–171 (1976)
Roth, R. H., Walters, J. R., Aghajanian, G. K.: Effects of impulse flow on the release and synthesis of dopamine in the rate striatum. In: Catecholamine research (E. Usdin, S. Snyder, eds.), pp. 267. New York: Pergamon Press 1973
Spano, P. F., Tagliamonte, A., Tagliamonte, P., Gessa, G. L.: Stimulation of brain dopamine synthesis by γ-hydroxybutyrate. J. Neurochem. 18, 1831–1836 (1971)
Stock, G., Magnusson, T., Andén, N.-E.: Increase in brain dopamine after axotomy or treatment with γ-hydroxybutyric acid due to elimination of the nerve impulse flow. Naunyn-Schmiedeberg's Arch. Pharmacol. 278, 347–361 (1973)
Tarsy, D., Baldessarini, R. J.: Pharmacologically induced behavioral supersensitivity to apomorphine. Nature New Biol. 245, 262–263 (1973)
Ungerstedt, U.: Postsynaptic supersensitivity after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system. Acta Physiol. Scand. Suppl. 367 (1971)
Walters, J. R., Roth, R. H.: Effect of γ-hydroxybutyrate on dopamine and dopamine metabolites in the rat striatum. Biochem. Pharmacol. 21, 2111–2121 (1972)
Walters, J. R., Roth, R. H.: Dopaminergic neurons: drug-induced antagonism of the increase in tyrosine hydroxylase activity produced by cessation of impulse flow. J. Pharmacol. Exp. Ther. 191, 82–91 (1974)
Walters, J. R., Roth, R. H.: Dopaminergic neurons: An in vivo system for measuring drug interactions with presynaptic receptors. Naunyn-Schmiedeberg's Arch. Pharmacol. 296, 5–14 (1976)
Walters, J. R., Aghajanian, G. K., Roth, R. H: Dopaminergic neurons: Inhibition of firing by γ-hydroxybutyrate. Proc. Fifth Cong. Pharmacol., p. 246, 1972
Walters, J. R., Roth, R. H., Aghajanian, G. K.: Dopaminergic neurons: similar biochemical and histochemical effects of gamma-hydroxybutyrate and acute lesions of the nigroneostriatal pathway. J. Pharmacol. Exp. Ther. 186, 630–639 (1973)
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Nowycky, M.C., Roth, R.H. Chronic gamma-butyrolactone (GBL) treatment: A potential model of dopamine hypoactivity. Naunyn-Schmiedeberg's Arch. Pharmacol. 309, 247–254 (1979). https://doi.org/10.1007/BF00504757
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DOI: https://doi.org/10.1007/BF00504757