Skip to main content
SpringerLink
Log in

Acute and chronic effects of 4-chloroamphetamine on monoamine metabolism in the rat brain

  • Published:
Psychopharmacologia Aims and scope Submit manuscript

Abstract

The acute administration of 4-chloroamphetamine caused a marked reduction in the concentration of serotonin and 5-hydroxyindoleacetic acid and a rise in dopamine in the rat brain. Following the injection of 3H-tyrosine and 3H-tryptophane into rats treated with 4-chloroamphetamine, there was a reduction in brain levels of 3H-dopamine and 3H-serotonin. Although the endogenous concentration of noradrenaline was not affected by 4-chloroamphetamine, there is evidence that its reuptake into neurones was reduced and its release increased by the drug. Following the administration of 4-chloroamphetamine for 10 days, the concentration of 5-hydroxyindoleacetic acid was reduced; no other changes in amine metabolism were apparent. From this investigation, and those of others, it appears that following acute administration, 4-chloroamphetamine has a neurochemical profile which has a similarity to that of many tricyclic antidepressants. However, there is a marked discrepancy between the acute and chronic effects of 4-CA on brain amine metabolism. Such findings are difficult to reconcile with the widely accepted theory that antidepressant drugs counteract the symptoms of depression by increasing the concentration of noradrenaline and/or serotonin at receptor sites within the brain.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Anden, N.-E., Atack, C. V., Srensson, T. H.: Release of dopamine from central noradrenergic and dopaminergic nerves induced by a dopamine Β-hydroxylase inhibitor. J. Pharmacol. exp. Ther. 138, 360–375 (1962)

    Google Scholar 

  • Anton, A. H., Sayre, D. F.: The distribution of dopamine and dopa in various animals and a method for their determination in diverse biological material. J. Pharmacol. exp. Ther. 145, 326–336 (1964)

    Google Scholar 

  • Anton, A. H., Sayre, D. F.: Distribution of metanephrine and normetanephrine in various animals and their analysis in diverse biological material. J. Pharmacol. exp. Ther. 153, 15–19 (1966)

    Google Scholar 

  • Bunney, W. E., Davis, J. M.: Norepinephrine in depressive reactions. Arch. gen. Psychiat. 13, 483–494 (1965)

    Google Scholar 

  • Carlsson, A., Fuxe, K., Hamberger, B., Malmfors, T.: Effect of a new series of bicyclic compounds with potential thymoleptic properties on the reserpine resistant uptake mechanisms of central and peripheral monoamine neurones in vivo and in vitro. Brit. J. Pharmacol. 36, 18–28 (1969)

    Google Scholar 

  • Carlsson, A., Lindquist, M., Dahlstrom, A., Fuxe, K., Masuoka, D.: Effects of the amphetamine group on intraneuronal brain amines in vivo and in vitro. J. Pharm. Pharmacol. 17, 521–524 (1965)

    Google Scholar 

  • Coppen, A.: Indoleamines and affective disorders. J. psychiat. Res. 9, 163–172 (1972)

    Google Scholar 

  • Coppen, A., Shaw, D. M., Farrell, J. P.: Potentiation of the antidepressive effect of a monoamine oxidase inhibitor by tryptophan. Lancet 1963I, 79–81

    Google Scholar 

  • Costa, E., Naimzada, K. M., Revuelta, A.: Effect of phenmetrazine, aminorex and (±)-p-chloroamphetamine on the motoractivity and turnover rate of brain catecholamines. Brit. J. Pharmacol. 43, 570–579 (1971)

    Google Scholar 

  • Costa, E., Revuelta, A.: (−)p-Chloroamphetamine and serotonin turnover in rat brain. Neuropharmacology 11, 291–295 (1972)

    Google Scholar 

  • Curzon, G., Green, A. R.: Rapid method for the determination of 5-hydroxytryptophan and 5-hydroxyindoleacetic acid in small regions of the rat brain. Brit. J. Pharmacol. 39, 653–655 (1970)

    Google Scholar 

  • Fuller, R. W.: Serotonin oxidation by rat brain monoamine oxidase: inhibition by 4-chloroamphetamine. Life Sci. 5, 2247–2257 (1966)

    Google Scholar 

  • Fuller, R. W., Hines, C. W., Mills, J.: Lowering of brain serotonin level by chloramphetamines. Biochem. Pharmacol. 14, 483–488 (1965)

    Google Scholar 

  • Fuller, R. W., Schaffer, R. J., Roush, B. W., Molloy, B. B.: Drug disposition as a factor in the lowering of brain serotonin by chloramphetamines in the rat. Biochem. Pharmacol. 21, 1413–1417 (1972)

    Google Scholar 

  • Giacolone, E., Valzelli, L.: A method for the determination of 5-hydroxyindolyl-3-acetic acid in brain. J. Neurochem. 13, 1265–1266 (1966)

    Google Scholar 

  • Guroff, G., King, W., Udenfriend, S.: The uptake of tyrosine by rat brain in vitro. J. biol. Chem. 236, 1733–1777 (1961)

    Google Scholar 

  • Hess, S., Udenfriend, S.: A fluorimetric procedure for the measurement of tryptamine in tissues. J. Pharmacol. exp. Ther. 127, 175–177 (1959)

    Google Scholar 

  • Lapin, T. P., Oxenkrug, G. F.: Intensification of the ventral serotonergic processes as a possible determinant of the thymoleptic effect. Lancet 1969I, 132–136

    Google Scholar 

  • Lassen, J. B.: The effect of p-chloroamphetamine on motility in rats after inhibition of monoamine synthesis, storage, uptake and receptor inactivation. Psychopharmacologia (Berl.) 34, 243–254 (1974)

    Google Scholar 

  • Leonard, B. E.: Effect of four amphetamines on brain biogenic amines and their metabolites. Biochem. Pharmacol. 21, 1289–1297 (1972)

    Google Scholar 

  • Leonard, B. E., Shallice, S. A.: Some neurochemical effects of amphetamine: methylamphetamine and p-bromomethylamphetamine in the rat. Brit. J. Pharmacol. 41, 198–212 (1971)

    Google Scholar 

  • Leonard, B. E., Shallice, S. A.: The effect of some tryptamine derivatives on brain monoamines and their precursor amino acids. Neuropharmacology 11, 373–384 (1972)

    Google Scholar 

  • Leonard, B. E., Tonge, S. R.: The effects of some hallucinogenic drugs upon the metabolism of noradrenaline. Life Sci. 8, 815–825 (1969)

    Google Scholar 

  • Miller, F. P., Cox, R. H., Snodgrass, W. R., Maickel, R. P.: Comparative effects of p-chlorophenylalanine, p-chloroamphetamine and p-chloro-N-methylamphetamine on rat brain norepinephrine, serotonin and 5-hydroxyindole-3-acetic acid. Biochem. Pharmacol. 19, 435–442 (1970)

    Google Scholar 

  • Moore, K. E., Lariviere, E. W.: Effects of d-amphetamine and restraint on the content of norepinephrine and dopamine in the rat brain. Biochem. Pharmacol. 12, 1283–1288 (1963)

    Google Scholar 

  • Neff, N. H., Spano, P. F., Groppetti, A., Wang, C. T., Costa, E.: A simple procedure for calculating the synthesis rate of norepinephrine dopamine and serotonin in rat brain. J. Pharmacol. exp. Ther. 176, 701–710 (1971)

    Google Scholar 

  • Pletscher, A., Bartholini, G., Bruderer, H., Burkard, W. P., Gey, K. F.: Chlorinated arylalkylamines affecting the cerebral metabolism of 5-hydroxytryptamine. J. Pharmacol. exp. Ther. 145, 344–350 (1964)

    Google Scholar 

  • Pletscher, A., Da Prada, M., Burkard, W. P., Bartholini, G., Steiner, F. A., Bruderer, H., Bigler, F.: Aralkylamines with different effects on the metabolism of aromatic monoamines. J. Pharmacol. exp. Ther. 154, 64–72 (1966)

    Google Scholar 

  • Van Praag, H. M., Kits, T. P., Schut, J., Dijkstra, P.: An attempt at indirect evaluation of the noradrenaline hypothesis. Results of a pilot study of the antidepressive qualities of a p-chloro-N-methylamphetamine. Psychiat. Neurol. Neurochir. 72, 181–187 (1969)

    Google Scholar 

  • Van Praag, H. M., Korf, J.: 4-Chloramphetamines. Chance and trend in the development of new antidepressants. J. clin. Pharmacol. 13, 3–14 (1973)

    Google Scholar 

  • Van Praag, H. M., Korf, J., van Woudenberg, F.: Investigation into the possible influence of chlorinated amphetamine derivatives on 5-hydroxytryptamine synthesis in man. Psychopharmacologia (Berl.) 18, 412–420 (1970)

    Google Scholar 

  • Van Praag, H. M., Korf, J., van Woudenberg, F., Kits, T. P.: Influencing the human indoleamine metabolism by means of a chlorinated amphetamine derivative with anti-depressant action (p-chloro-N-methylamphetamine). Psychopharmacologia (Berl.) 13, 145–160 (1968)

    Google Scholar 

  • Sanders-Bush, E., Bushing, J. A., Sulser, F.: Long term effects of p-chloroamphetamine of tryptophan hydroxylase activity and on the levels of 5-hydroxytryptamine and 5-hydroxytryptamine acid in brain. Europ. J. Pharmacol. 20, 385–388 (1972)

    Google Scholar 

  • Scheel-Krüger, J.: Behavioural and biochemical comparison of amphetamine derivatives, cocaine benztropine and tricyclic anti-depressant drugs. Europ. J. Pharmacol. 18, 63–73 (1972)

    Google Scholar 

  • Schildkraut, J. J.: The catecholamine hypothesis of affective disorders: a review of supporting evidence. Amer. J. Psychiat. 122, 509–533 (1965)

    Google Scholar 

  • Schildkraut, J. J., Draskoczy, P. R., Gershon, E. S., Reich, P., Grab, E. L.: Catecholamine metabolism in affective disorders. IV. Preliminary studies of norephinephrine metabolism in depressed patients treated with amitriptyline. J. psychiat. Res. 9, 173–186 (1972)

    Google Scholar 

  • Strada, S. J., Sanders-Bush, E., Sulser, F.: p-Chloroamphetamine: in vivo investigations on the mechanism of action of the selective depletion of cerebral serotonin. J. Pharmacol. exp. Ther. 175, 419–426 (1970)

    Google Scholar 

  • Tagliamonte, A., Tagliamonte, P., Perez-Cruet, J., Stern, S., Gessa, G. L.: Increase of brain tryptophan caused by drugs which stimulate serotonin synthesis. Nature 229, 125–126 (1971)

    Google Scholar 

  • Wong, D. T., van Frank, R. M., Horng, J.-S., Fuller, R. W.: Accumulation of amphetamine and p-chloroamphetamine into synaptosomes of rat brain. J. Pharm. Pharmacol. 24, 171–173 (1972)

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pharmacology Department, Scientific Development Group, Organon International B.V., Oss, The Netherlands

    B. E. Leonard

  2. Department of Pharmacology, University College, Galway, Ireland

    B. E. Leonard

Authors
  1. B. E. Leonard
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Leonard, B.E. Acute and chronic effects of 4-chloroamphetamine on monoamine metabolism in the rat brain. Psychopharmacologia 46, 11–18 (1976). https://doi.org/10.1007/BF00421543

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00421543

Key words

Search

Navigation