Summary
Unilateral stereotaxic injections of 1 μg of the soluble benzodiazepine chlordiazepoxide hydrochloride into the predominantly GABA-containing zona reticulata of the substantia nigra of amphetamine-pretreated rats induced rotational behaviour similar to that seen following unilateral elevation of nigral GABA levels and amphetamine treatment; this effect was not seen following injections into the vicinity of the predominantly dopamine-containing zona compacta. Chlordiazepoxide-induced rotations were abolished by the GABA-antagonist picrotoxin. Both chlordiazepoxide and GABA depressed production of cyclic 3′,5′-guanosine monophosphate in samples of nigral tissue in vitro as estimated by radioimmunoassay. It is concluded that chlordiazepoxide may enhance GABA transmission within the substantia nigra, by some as yet unidentified mechanism, to create asymmetric activity in GABA-modulated neurones and hence induce rotation.
Similar content being viewed by others
References
Andén, N.-E., Stock, G.: Inhibitory effect of gammahydroxy-butyric acid and gammaaminobutyric acid on the dopamine cells in the substantia nigra. Naunyn-Schmiedeberg's Arch. Pharmacol. 279, 89–92 (1973)
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)
Cheramy, A., Nieoullon, A., Glowinski, J.: Blockade of the picrotoxin-induced in vivo release of dopamine in the cat caudate nucleus by diazepam. Life Sci. 20, 811–816 (1977)
Costa, E., Guidotti, A., Mao, C. C.: Evidence for involvement of GABA in the action of benzodiazepines: studies on rat cerebellum. In: Mechanism of action of benzodiazepines (E. Costa and P. Greengard, eds.), pp. 113–130. New York: Raven Press 1975a
Costa, E., Guidotti, A., Mao, C. C., Suria, A.: New concepts on the mechanism of action of benzodiazepines. Life Sci. 17, 167–186 (1975b)
Costall, B., Marsden, C. D., Naylor, R. J., Pycock, C. J.: The relationship between striatal and mesolimbic dopamine dysfunction and the nature of circling responses following 6-hydroxydopamine and electrolytic lesions of the ascending dopamine systems of rat brain. Brain Res. 118, 87–113 (1976)
Dray, A., Straughan, D. W.: Synaptic mechanisms in the substantia nigra. J. Pharm. Pharmacol. 28, 400–405 (1976)
Dray, A., Oakley, N. R., Simmonds, M. A.: Rotational behaviour following inhibition of GABA metabolism unilaterally in the rat substantia nigra. J. Pharm. Pharmacol. 27, 627–628 (1975a)
Dray, A., Fowler, L. J., Oakley, N. R., Simmonds, M. A., Tanner, T.: Comparison of circling behaviour following unilateral inhibition of GABA-transaminase or discrete electrolytic lesioning in the rat substantia nigra. Br. J. Pharmacol. 55, 288P (1975b)
Dray, A., Goyne, T. J., Oakley, N. R.: Candate stimulation and substantia nigra activity in the rat. J. Physiol. (Lond.) 259, 825–849 (1976)
Gähwiler, B. H.: Diazepam and chlordiazepoxide: powerful GABA antagonists in explants of rat cerebellum. Brain Res. 107, 176–179 (1976)
Glick, S. D., Jerussi, T. P., Fleisher, L. N.: Turning in circles: the neuropharmacology of rotation. Life Sci. 18, 889–896 (1976)
Gumulka, S. W., Dinnendahl, V., Peters, H. D., Schönhöfer, P. S.: Effects of dopaminergic stimulants on cyclic nucleotide levels in mouse brain in vivo. Naunyn-Schmiedeberg's Arch. Pharmacol. 293, 75–80 (1976)
Haefely, W., Kulcsar, 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
Kanazawa, I., Miyata, Y., Toyokura, Y., Otsuka, M.: The distribution of γ-aminobutyric acid (GABA) in the human substantia nigra. Brain Res. 51, 363–365 (1973)
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)
Kimura, H., Mittal, C. K., Murad, F.: Increase in cyclic GMP levels in brain and liver with sodium azide an activator of guanylate cyclase. Nature 257, 700–702 (1975)
Kinscherf, D. A., Chang, M. M., Rubin, E. H., Schneider, D. R., Ferrendelli, J. A.: Comparison of the effects of depolarising agents and neurotransmitters on regional CNS cyclic GMP levels in various animals. J. Neurochem. 26, 527–530 (1976)
König, J. F. R., Klippel, R. A.: The rat brain: a stereotaxic atlas of the forebrain and lower parts of the brainstem. Baltimore: Williams and Wilkins 1963
Koob, G., Del Fiacco, M., Iversen, S. D.: The behavioural effects of EOS-induced changes in substantia nigra GABA levels. Br. J. Pharmacol. 58, 454P (1976)
Lowry, O. H., Rosebrough, N. J., Farr, A. L., Randall, R. J.: Protein measurement with Folin phenol reagent. J. Biol. Chem. 193, 265–275 (1951)
Oberlander, C., Dumont, C., Boissier, J. R.: Rotational behaviour after unilateral intranigral injection of muscimol in rats. Eur. J. Pharmacol. 43, 389–390 (1977)
Paden, C., Wilson, C. J., Groves, P. M.: Amphetamine-induced release of dopamine from the substantia nigra in vitro. Life Sci. 19, 1499–1506
Precht, W., Yoshida, M.: Blockage of caudate-evoked inhibition of neurones in the substantia nigra by picrotoxin. Brain Res. 32, 229–233 (1971)
Soubrie, P., Simon, P., Boissier, J. R.: Antagonism of diazepam against central anticholinergic drug-induced hyperactivity in mice: Involvement of a GABA mechanism. Neuropharmacology 15, 773–776 (1976)
Stein, L., Wise, C. D., Belluzzi, J. D.: Effects of benzodiazepines on central serotonergic mechanisms. In: Mechanism of action of benzodiazepines (E. Costa and P. Greengard, eds.), pp. 29–44. New York: Raven Press 1975
Steiner, A. L., Ferendelli, J. A., Kipnis, D. M.: Effect of ischemia, changes during development and regional distribution of adenosine 3′,5′-monophosphate and guanosine 3′,5′-monophosphate. in mouse brain. J. Biol. Chem. 247, 1121–1124 (1972)
Steiner, F. A., Felix, D.: Antagonistic effects of GABA and benzodiazepines on vestibular and cerebellar neurones. Nature 260, 346–347 (1976)
Tappaz, M. L., Brownstein, M. J., Palkovist, M.: Distribution of glutamate decarboxylase in discrete brain nucler. Brain Res. 108, 371–379 (1976)
Ungerstedt, U.: Stereotaxic mapping of the monoamine pathways in the rat brain. Acta Physiol. Scand., Suppl. 367, 1–48 (1971)
Ungerstedt, U., Arbuthnott, G. W.: Quantitative recording of rotational behaviour in rats after 6-hydroxydopamine lesions of the nigrostriatal dopamine system. Brain Res. 24, 485–493 (1970)
Waddington, J. L.: A behavioural model of the GABA-facilitating action of benzodiazepines: rotational behaviour after unilateral intranigral injection of chlordiazepoxide. Br. J. Pharmacol. 58, 453P (1976)
Waddington, J. L.: GABA-like properties of flurazepam and baclofen suggested by rotational behaviour following unilateral intranigral injection: a comparison with the GABA agonist muscimol. Br. J. Pharmacol. 60, 263P-264P (1977)
Yoshida, M., Precht, W.: Monosynaptic inhibition of neurones in the substantia nigra by caudate-nigral fibres. Brain Res. 32, 225–228 (1971)
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Waddington, J.L., Longden, A. Rotational behaviour and cGMP responses following manipulation of nigral mechanisms with chlordiazepoxide. Naunyn-Schmiedeberg's Arch. Pharmacol. 300, 233–237 (1977). https://doi.org/10.1007/BF00500965
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00500965