Summary
The behavioural and biochemical effects of racemic 3-PPP (3-[3-hydroxyphenyl]-N-n-propyl-piperidine) and its enantiomers was studied in developing rats, aged 1–28 days. All three compounds exhibit dopamine (DA) autoreceptor-stimulating properties. Moreover, the (+)-enantiomer displays agonist and the (−)-enantiomer antagonist actions, respectively, on the postsynaptic DA receptor. This means that the racemate has a DA autoreceptor stimulatory action with slight or no effects on the postsynaptic receptor.
Locomotor experiments demonstrated that (±)-3-PPP inhibited spontaneous locomotor activity dosedependently in the 28 days old rats. No effects were seen in the age groups 14 days and younger. While the racemate and the (−)-enantiomer inhibited spontaneous locomotor activity in 28 days old rats, the (+)-enantiomer had no effects compared to saline. Interestingly, the (+)-enantiomer increased locomotor activity in the 4 days old rats, while the (−)-enantiomer and the racemate did not induce any effects.
In the biochemical experiments, after blockade of DA neurotransmission with gamma-butyrolactone (GBL), (±)-3-PPP inhibited the increase in tyrosine hydroxylase activity (DOPA accumulation after NSD 1015) after GBL in the DA rich striatum region of the 28 days but not of the 4 days old rats.
From these experiments it may be concluded that functional postsynaptic but not presynaptic DA receptors exist in the brain af 4 days old rats. Presynaptic DA receptors do not seem to be functionally mature until 28 days postnatally in the rat, i.e. during adolescent age.
Similar content being viewed by others
References
Arnt, J.: Differential behavioural effects of dopamine agonists in developing rats: A study of 3-PPP enantiomers. Eur. J. Pharmacol.91, 273 (1983).
Arvidsson, L.-E., Hacksell, U., Johansson, A., Nilsson, J. L. G., Sanchez, D., Wikström, H., Lindberg, P., Hjort, S., Svensson, K., Carlsson, A.: 3-Phenylpiperidines. Central dopamine autoreceptor stimulation activity: (+)-and (−)-3-PPP. Acta Pharm. Suec, Suppl.2, 184–185 (1983).
Carlsson, A.: Dopaminergic autoreceptors. In: Chemical Tools in Catecholamine Research (Almgren, O., Carlsson, A., Engel, J., eds.), Vol. II, pp. 219–224. North-Holland 1975.
Carlsson, A., Davis, J. N., Kehr, W., Lindqvist, M., Atack, C. V.: Simultaneous measurement of tyrosine and tryptophan hydroxylase activities in brainin vivo using an inhibitor of the aromatic amino acid decarboxylase. Naunyn-Schmiedberg's Arch. Pharmacol.275, 153–168 (1972).
Carlsson, A., Kehr, W., Lindqvist, M.: The role of intraneuronal amine levels in the feed-back control of dopamine, noradrenaline and 5-hydroxytryptamine synthesis in rat brain. J. Neural Transm.39, 1–19 (1976).
Carlsson, A., Lindqvist, M.: Effects of ethanol on the hydroxylation of tyrosine and tryptophan in rat brainin vivo. J. Pharm. Pharmacol.25, 437–440 (1973).
Cheronis, J., Erinoff, L., Heller, A., Hoffmann, P.: Pharmacological analysis of the nigrostriatal dopaminergic neurons. Brain Res.169, 545–560 (1979).
Cools, A. R., Van Rossum, J. M.: Excitation — mediating dopamine-receptors: A new concept towards a better understanding of electrophysiological, biochemical, pharmacological, functional and clinical data. Psychopharmacol.45, 242–254 (1976).
Coyle, J. T.: Development of the central catecholamine neurons in the rat. In: Frontiers in Catecholamine Research (Usdin, E., Snyder, S., eds.), pp. 261–265. Oxford-New York: Pergamon Press. 1973.
Creese, I.: Dopamine receptors explained. TIPS, 1982, 40–43.
Di Chiara, G., Corsini, G. U., Mereu, G. P., Tissari, A., Gessa, G. L.: Self-inhibitory dopamine receptors: Their role in the biochemical and behavioural effects of low doses of apomorphine. In: Adv. Biochem. Psychopharmacol. (Roberts, P. J. et al., eds.), Vol. 19, pp. 275–292. New York: Raven Press. 1978.
Engström, G., Svensson, T. H., Waldeck, B.: Thyroxine and brain catecholamines: increased transmitter synthesis and increased receptor sensitivity. Brain Res.77, 471–483 (1974).
Felice, L. J., Felice, J. D., Kissinger, P. T.: Determination of catecholamines in rat brain parts by reverse-phase ion-pair liquid chromatography. J. Neurochem.31, 1461–1465 (1978).
Hacksell, U., Arvidsson, L.-E., Svensson, U., Nilsson, J. L. G., Sanchez, D., Wikström, H., Lindberg, P., Hjort, S., Carlsson, A.: 3-Phenylpiperidines. Central dopamine-autoreceptor stimulating activity. J. Med. Chem.24, 1475–1482 (1981).
Hedner, T., Lundborg, P.: Neurochemical characteristics of cerebral catecholamine neurons during the postnatal development in the rat. Medical. Biol.59, 212–223 (1981).
Hedner, T., Lundborg, P.: Effect of gamma-hydroxybutyric acid on catecholamine synthesis and utilization in the developing rat brain. J. Neural Transm.54, 19–28 (1982).
Hedner, T., Lundborg, P.: Autoregulation of catecholamine neurons in the developing rat brain (in manuscript).
Hjorth, S.: On the mode of action of 3-(3-hydroxyphenyl)-N-n-propylpiperidine, 3-PPP, and ist enantiomers. Gotab (Göteborg), 1–52 (1983).
Kebabian, J. W., Calne, D. B.: Multiple receptors for dopamine. Nature277, 93–96 (1979).
Kellogg, C., Lundborg, P.: Ontogenetic variations in responses to L-DOPA and monoamine receptor stimulating agents. Psychopharmacol.23, 187–200 (1972).
Kellogg, C., Lundborg, P.: Inhibition of catecholamine synthesis during ontogenetic development. Brain Res.61, 321–329 (1973).
Kellogg, C., Wennerström, G.: An ontogenetic study on the effect of catecholamine receptor stimulating agents on the turnover in the brain. Brain Res.79, 451–464 (1974).
Lundborg, P., Hedner, T., Engel, J.: Catecholamine concentration in the developing rat brain afterγ-hydroxybutyric acid. J. Neurochem.35, 425–429 (1980).
Magnusson, O., Nilsson, L. B., Westerlund, D.: Simultaneous determination of dopamine, dopac and homovanillic acid. Direct injection of supernatants from brain homogenates in a liquid chromatography-electrochemical detection system. J. Chromatogr.221, 237–247 (1980).
Nomura, Y., Naitoh, F., Segowa, T.: Regional changes in monoamine content and uptake of the rat brain during postnatal development. Brain Res.101, 305–315 (1976).
Nowycky, M. C., Roth, R. H.: Dopaminergic neurons. Role of presynaptic receptors in the regulation of transmitter biosynthesis. Progr. Neuro-Psychopharmacol.2, 139–158 (1978).
Roth, R. H.: Dopamine autoreceptors: Pharmacology, function and comparison with post-synaptic dopamine receptors. Commun. Psychopharmacol.3, 429–445 (1979).
Seeman, P.: Brain dopamine receptors. Pharmacol. Rev.32, 229–313 (1980).
Shalaby, I. A., Denel, P. S., Spear, L. P.: Differential functional ontogeny of dopamine presynaptic regulation. Develop. Brain Res.1, 434–439 (1981).
Shum, A., Sole, M. J., van Loon, G. R.: Simultaneous measurements of 5-hydroxytryptophan and L-dihydroxyphenyl-alanine by high-performance liquid chromoatography with electrochemical detection. Measurement of serotonin and catecholamine turnover in discrete brain regions. J. Chromatogr.228, 123–130 (1982).
Sokoloff, P., Martes, M.-P., Schwartz, J. C.: Three classes of dopamine receptors (D-2, D-3, D-4) identified by binding studies with3H-apomorphine and3H-domperidone. Naunyn-Schmiedeberg's Arch. Pharmacol.315, 89–102 (1980).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Hedner, T., Lundborg, P. Development of dopamine autoreceptors in the postnatal rat brain. J. Neural Transmission 62, 53–63 (1985). https://doi.org/10.1007/BF01260415
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF01260415