Summary
Systemic administration of haloperidol to rats failed to alter the concentration of dopamine but increased the concentration of 3, 4-dihydroxy-phenylacetic acid (DOPAC), the major metabolite of dopamine, in both the striatum and substantia nigra. These haloperidol-induced changes in DOPAC were prevented by an intranigral microinjection of baclofen, a drug which reduces nigrostriatal dopaminergic neuronal activity.
It has been proposed that nigrostriatal neurons are regulated, in part, by the activation of autoreceptors in substantia nigra. However, intranigral microinjections of high concentrations of several dopaminergic antagonists failed to mimic the biochemical effects resulting from systemic administration of these drugs; instead, they slightly increased the concentrations of both dopamine and DOPAC in the striatum and decreased dopamine in substantia nigra. Intranigral microinjections of the dopamine agonist, apomorphine, failed to alter the concentration of DOPAC in the striatum, but reduced both dopamine and DOPAC in the nigra. If DOPAC concentrations reflect nigrostriatal dopaminergic neuronal activity, the present results suggest that dopaminergic agonists and antagonists acting in substantia nigra do not exert a major influence on the activity of these neurons.
Similar content being viewed by others
References
Aghajanian, G. K., Bunney, B. S. Central dopaminergic neurons: Neurophysiological identification and responses to drugs. In: Frontiers in Catecholamine Research (Usdin, E., Snyder, S., eds.), pp. 643–648. New York: Pergamon Press. 1973.
Algeri, S., Brunello, N., Calderini, G., Consolazione, A. Effect of enkephalins on catecholamine metabolism in rat CNS. In: Advances in Psychopharmacology 18 (Costa, E., Trabucchi, M., eds.), pp. 199–200. New York: Raven Press. 1978.
Björklund, A., Lindvall, O. Dopamine in dendrites of substantia nigra neurons: Suggestions for a role in dendritic terminals. Brain Res.83, 531–537 (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., Llndqvist, M. Effect of chlorpromazine and haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol. Toxicol.20, 140–144 (1963).
Davies, J., Dray, A. Substance P in the substantia nigra. Brain Res.107, 623–627 (1976).
Di Chiara, G., Porceddu, M. L., Fratta, W., Gessa, G. L. Postsynaptic receptors are not essential for dopaminergic feedback regulation. Nature267, 270–272 (1977).
Fadda, F., Argiolas, A., Stephanini, E., Gessa, G. L. Differential effects of psychotropic drugs on dihydroxyphenylacetic acid (DOPAC) in the rat substantia nigra and caudate nucleus. Life Sci.21, 411–418 (1977).
Fjalland, B. Inhibition by neuroleptics of3H-GABA into rat brain synaptosomes. Acta Pharmacol. Toxicol.42, 73–76 (1978).
Garcia.-Munoz, M., Nicolaou, N. M., Tulloch, I. F., Wright, A. K., Arbuthnott, G. W. Feedback loop or output pathway in striato-nigral fibers? Nature265, 363–365 (1977).
Gianutsos, G., Moore, K. E. Increase in mouse brain dopamine content by baclofen: Effects of apomorphine and neuroleptics. Psychopharmacol.52, 217–221 (1977).
Groppetti, A., Algeri, S., Cattabeni, F., DiGuilio, A. M., Galii, C. L., Ponzio, F., Spano, P. F. Changes in specific activity of dopamine metabolites as evidence of a multiple compartmentation. J. Neurochem.28, 193–197 (1977).
Groves, P. M., Wilson, C. J., Young, S. J., Rebec, G. V. Self inhibition by dopaminergic neurons. Science190, 522–529 (1975).
Hefti, F., Lienhart, R., Lichtensteiger, W. Transmitter metabolism in substantia nigra after inhibition of dopaminergic neurons by butyrolactone. Nature263, 341–342 (1976).
Kelly, P. H., Moore, K. E. Dopamine concentrations in the rat brain following injection into the substantia nigra of baclofen,γ-aminobutyric acid,γ-hydroxybutyrate, apomorphine and amphetamine. Neuropharmacol.17, 169–174 (1977).
Kehr, W., Carlsson, A., Lindqvist, M. Catecholamine synthesis in rat brain after axotomy: Interaction between apomorphine and haloperidol. Naunyn-Schmiedeberg's Arch. Pharmacol.297, 111–117 (1977).
Korf, J., Zieleman, M., Westerink, B. H. C. Metabolism of dopamine in the substantia nigra after antidromic activation. Brain Res.120, 184 to 187 (1977).
Lowry, O., Rosebrough, N. J., Farr, A. L., Randall, R. J. Protein measurement with Polin phenol reagent. J. Biol. Chem.193, 265–275 (1951).
Maggi, A., Bruno, F., Cattabeni, F., Groppetti, A., Parenti, M. Apomorphine-induced inhibition of striatal dopamine release: role of dopaminergic receptors in substantia nigra. Brain Res.145, 180–184 (1978).
Moore, R. Y., Bloom, F. E. Central catecholamine neuron systems: Anatomy and physiology of the dopamine systems. Ann. Rev. Neurosci.1, 129 to 169 (1978).
Nieoullon, A., Cheramy, A., Glowinski, J. Nigral and striatal dopamine release under sensory stimuli. Nature269, 340–342 (1977).
Olpe, H.-R., Koella, W. P., Wolf, P., Haas, H. L. The action of baclofen on neurons of the substantia nigra and of the ventral tegmental area. Brain Res.134, 577–580 (1977).
Pellegrino, L. J., Cushman, A. A stereotaxic atlas of the rat brain. New York: Appleton-Century-Crofts. 1967.
Pericic, D., Walters, J. R. Dopamine in the substantia nigra and cortex afterγ-butyrolactone treatment. J. Pharm. Pharmacol.28, 527–530 (1976).
Racagni, G., Bruno, F., Cattabeni, F., Maggi, A., DiGuilio, A. M., Parenti, M., Groppetti, A. Functional interaction between rat substantia nigra and dopamine interrelation. Brain Res.134, 353–358 (1977).
Roth, R. H., Murrin, L. C., Walters, J. R. Central dopaminergic neurons: Effects of alterations in impulse flow in the accumulation of dihydroxy-phenylacetic acid. Eur. J. Pharmacol.36, 163–172 (1976).
Roth, R. H., Walters, J. R., Agbajanian, G. K. Effect of impulse flow on the release and synthesis of dopamine in the rat striatum. In: Frontiers in Catecholamine Research (Usdin, E., Snyder, S., eds.), pp. 567–574. New York: Pergamon Press. 1973.
Sokol, R. R., Rohlf, F. J. Biometry, pp. 328–333. San Francisco: W. H. Freeman and Co. 1969.
Umezu, K., Moore, K. E.: Effects of drugs on regional brain concentrations of dopamine and DOPAC. J. Pharmacol. Exp. Ther. (in press, 1979).
Waldmeier, P. C., Maitre, L. Effects of baclofen on dopamine metabolism and interaction with neuroleptic effects. Eur. J. Pharmacol.47, 191 to 200 (1978).
Walters, J. R., Roth, R. H. Pre- and postsynaptic actions of antipsychotic drugs. In: Antipsychotic Drugs: Pharmacodynamics and Pharmacokinetics (Sedvall, G., ed.), pp. 147–160. Oxford: Pergamon Press. 1975.
Walters, J. R., Roth, R. H. Dopaminergic neurons-alteration in the sensitivity of tyrosine hydroxylase to inhibition by endogenous dopamine after cessation of impulse flow. Biochem. Pharmacol.25, 649–654 (1976).
Wuerthele, S. M., Kelly, P. H., Moore, K. E. Biochemical properties of nigrostriatal dopaminergic neurons following intrastriatal administration of kainic acid. The Pharmacologist19, 223 (1977).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Wuerthele, S.M., Friedle, N.M. & Moore, K.E. Effects of intranigral administration of dopamine agonists and antagonists and baclofen on concentrations of dopac and dopamine in the striatum and substantia nigra of the rat. J. Neural Transmission 45, 117–127 (1979). https://doi.org/10.1007/BF01250087
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF01250087