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A pharmacological study of changes in central nervous system receptor responsiveness after long-term dexamphetamine and apomorphine administration

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Abstract

Mice administered dexamphetamine (4 mg/kg i.p.) once daily for 20 days displayed an enhanced locomotor response (compared to that of vehicletreated mice) to dexamphetamine when challenged 4 to 16 days but not when challenged 32 days after withdrawal.

In the experiments described a 20-day dexamphetamine administration followed by an 8-day withdrawal period was used. Pimozide or haloperidol not only completely antagonised the enhanced response to dexamphetamine (2 mg/kg i.p.) in dexamphetamine-treated mice, but also antagonised all dexamphetamine-induced stimulation. Reserpine, in contrast, preferentially blocked the difference in the response to dexamphetamine of dexamphetamine-and vehicle-treated mice, without antagonising all the dexamphetamine-induced locomotion. The stimulation produced in dexamphetamine-(but not in vehicle-) treated mice by dexamphetamine was partially blocked by phentolamine, phenoxybenzamine, and propranolol. FLA-63 did not significantly influence the response to dexamphetamine in either group. That a dopaminergic mechanism plays a major role in the enhanced response to dexamphetamine was shown by the significantly greater response in dexamphetamine-treated mice to apomorphine challenge.

The treatment of mice with apomorphine (10 mg/kg/day i.p. for 20 days), produced a greater response to apomorphine challenge in the apomorphine-treated mice than in vehicle-treated mice 8 days after withdrawal.

The data show that with long-term administration both dexamphetamine and apomorphine are able to produce in mice what appear to be supersensitive dopamine receptors. Moreover, the enhanced response to dexamphetamine after withdrawal from long-term dexamphetamine treatment appears to require the presence of reserpine-sensitive amine stores and, to a lesser extent, the presence of unblocked α-adrenergic receptors.

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References

  • Andén, N.-E.: Pharmacological and anatomical implications of induced abnormal movements with l-Dopa. In: l-Dopa and Parkinsonism, A. Barbeau and F. H. McDowell, eds., pp. 132–143, Philadelphia: Davis 1970

    Google Scholar 

  • Andén, N.-E., Butcher, S. G., Corrodi, H., Fuxe, K., Ungerstedt, U.: Receptor activity and turnover of dopamine and noradrenaline after neuroleptics. Eur. J. Pharmacol. 11, 303–314 (1970)

    Google Scholar 

  • Andén, N.-E., Rubenson, A., Fuxe, K., Hökfelt, T.: Evidence for dopamine receptor stimulation by apomorphine. J. Pharm. Pharmacol. 19, 627–629 (1967)

    Google Scholar 

  • Andén, N.-E., Strömbom, U., Svensson, T. H.: Dopamine and noradrenaline receptor stimulation: reversal of reserpine-induced suppression of motor activity. Psychopharmacologia (Berl.) 29, 289–298 (1973)

    Google Scholar 

  • Barbeau, A.: l-Dopa therapy in parkinson's disease: a critical review of nine years experience. Can. Med. Assoc. J. 101, 59–68 (1969)

    Google Scholar 

  • Baudry, M., Martres, M.-P., Schwartz, J.-C.: Modulation in the sensitivity of noradrenergic receptors in the CNS studied by the responsiveness of the cyclic AMP system. Brain Res. 116, 111–124 (1976)

    Google Scholar 

  • Brodie, B. B., Cho, A. K., Gessa, G. L.: Possible role of p-hydroxynorephedrine in the depletion of norepinephrine induced by d-amphetamine and in tolerance to this drug. In: Amphetamines and related compounds; Proceedings of the Mario Negri Institute for Pharmacological Research, Milan, Italy, E. Costa and S. Garattini, eds., pp. 217–230. New York: Raven Press 1970

    Google Scholar 

  • Burt, D. R., Creese, I., Snyder, S. H.: Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain. Science 196, 326–328 (1977)

    Google Scholar 

  • Carlsson, A.: Biochemical implications of Dopa-induced actions on the central nervous system, with particular reference to abnormal movements. In: l-Dopa and Parkinsonism, A. Barbeau and F. H. McDowell, eds., pp. 205–213. Philadelphia: Davis 1970a

    Google Scholar 

  • Carlsson, A.: Amphetamine and brain catecholamines. In: Amphetamines and related compounds: Proceedings of the Mario Negri Institute for Pharmacological Research. Milan, Italy, E. Costa, and S. Garattini, eds., pp. 289–300. New York: Raven Press 1970b

    Google Scholar 

  • Carlsson, A.: Dopaminergic autoreceptors. In: Chemical tools in catecholamine research, vol. II, O. Almgren, A. Carlsson, and J. Engel, eds., pp. 219–225. Amsterdam: North-Holland 1975

    Google Scholar 

  • Carlsson, A., Corrodi, H., Florvall, L., Ross, S.: The Swedish Patent Application 17198/1967 (1967)

  • Chiel, H., Yehuda, S., Wurtman, R. J.: Development of tolerance in rats to the hypothermic effects of d-amphetamine and apomorphine. Life Sci. 14, 483–488 (1974)

    Google Scholar 

  • Costentin, J., Protais, P., Schwartz, J.-C.: Rapid and dissociated changes in sensitivities of different dopamine receptors in mouse brain. Nature 257, 405–407 (1975)

    Google Scholar 

  • Dunstan, R., Jackson, D. M.: The demonstration of a change in adrenergic receptor sensitivity in the central nervous system of mice after withdrawal from long-term treatment with haloperidol. Psychopharmacology 48, 105–114 (1976)

    Google Scholar 

  • Ellinwood, E. H.: “Accidental conditioning” with chronic meth-amphetamine intoxication: implication for a theory of drug habituation. Psychopharmacologia (Berl.) 21, 131–138 (1971)

    Google Scholar 

  • Engel, J., Liljeqvist, S., Johannessen, K.: Behavioural effects of long-term treatment with antipsychotic drugs. In: Antipsychotic drugs, pharmacodynamics and pharmacokimetics, Y. Zotterman, B. Uvnäs, and G. Sedvall, eds., pp. 63–71. New York: Pergamon Press 1976

    Google Scholar 

  • Fjalland, B., Møller-Nielsen, I.: Enhancement of methylphenidateinduced stereotypies by repeated administration of neuroleptics. Psychopharmacologia (Berl.) 34, 105–109 (1974)

    Google Scholar 

  • Herman, Z. S., Trzeciak, H., Chruściel, T. L., Kmieciak-Kolada, K., Drybański, A., Sokola, A.: The influence of prolonged amphetamine treatment and amphetamine withdrawal on brain biogenic amine content and behaviour in the rat. Psychopharmacologia (Berl.) 21, 74–81 (1971)

    Google Scholar 

  • Jackson, D. M.: The involvement of noradrenergic systems in the locomotor activity stimulation in mice produced by β-phenylethylamine. J. Pharm. Pharmacol. 26, 651–654 (1974)

    Google Scholar 

  • Jackson, D. M., Andén, N.-E., Engel, J., Liljeqvist, S.: The effect of long-term penfluridol treatment on the sensitivity of the dopamine receptors in the nucleus accumbens and in the corpus striatum. Psychopharmacologia (Berl.) 45, 151–155 (1975a)

    Google Scholar 

  • Jackson, D. M., Dunstan, R., Bracs, P. U.: Pharmacological models in tardive dyskinesia: a role for dopamine and noradrenaline? In: Drugs and psychiatry, G. F. S. Johnson, ed., pp. 13–21. Geigy Psychiatric Symposium, Sydney 1975b

  • Jacobsen, E.: Tranquillisers and sedatives. In: Evaluationof drug activities, pharmacometrics, vol. I, D. R. Laurence and A. L. Bacharach, eds., pp. 215–237. London: Academic Press 1964

    Google Scholar 

  • Klawans, H. L., Crossett, P., Dana, N.: Effect of chronic amphetamine exposure on stereotyped behaviour: implications for pathogenesis of l-Dopa-induced dyskinesias. In: Advances in neurology, Vol. 9, D. B. Calne, T. N. Chase, and A. Barbeau, eds., pp. 105–112. New York: Raven Press 1975b

    Google Scholar 

  • Klawans, H. L., Margolin, D. I.: Amphetamine-induced dopaminergic hypersensitivity in guinea pigs. Arch. Gen. Psychiatry 32, 725–732 (1975)

    Google Scholar 

  • Klawans, H. L., Margolin, D. I., Dana, N., Crossett, D.: Supersensitivity of d-amphetamine and apomorphine-induced stereotyped behaviour induced by chronic d-amphetamine administration. J. Neurol. Sci. 25, 283–289 (1975a)

    Google Scholar 

  • Klawans, H. L., Rubovits, R.: An experimental model of tardive dyskinesia. J. Neurol. Trans. 33, 235–246 (1972)

    Google Scholar 

  • Lewander, T.: Urinary excretion and tissue levels of catecholamines during chronic amphetamine intoxication. Psychopharmacologia (Berl.) 13, 394–407 (1968)

    Google Scholar 

  • Lewander, T.: Effects of acute and chronic amphetamine intoxication on brain catecholamines in the guinea pig. Acta Pharmacol. Toxicol. 29, 209–225 (1971)

    Google Scholar 

  • Markham, C. H.: The choreoathetoid movement disorder induced by levodopa. Clin. Pharmacol. Ther. 12, 340–346 (1971)

    Google Scholar 

  • Moore, K. E., Dominic, J. A.: Tyrosine hydroxylase inhibitors. Fed. Proc. 30, 859–870 (1971)

    Google Scholar 

  • Overstreet, D. H., Kozar, M. D., Lynch, G. S.: Reduced hypothermic effects of cholinomimetic agents following chronic anticholinesterase treatment. Neuropharmacol. 12, 1017–1032 (1973)

    Google Scholar 

  • Peachy, J. E., Rogers, B., Brien, J. F.: A comparative study of the behavioural responses induced by chronic administration of methamphetamine and amphetamine in mice. Psychopharmacology 51, 137–140 (1977)

    Google Scholar 

  • Rylander, G.: Psychoses and the punding and choreiform syndromes in addition to central stimulant drugs. Psychiatr. Neurol. Neurochir. 75, 203–213 (1972)

    Google Scholar 

  • Sahakian, B. J., Robbins, T. W., Iversen, S. D.: α-Flupenthixol induced hyperactivity by chronic dosing in rats. Eur. J. Pharmacol. 37, 169–178 (1976)

    Google Scholar 

  • Schelkunov, E. L.: Adrenergic effect of chronic administration of neuroleptics. Nature (Lond.) 214, 1210–1212 (1967)

    Google Scholar 

  • Segal, D. S., Mandell, A. J.: Long-term administration of d-amphetamine: progressive augmentation of motor activity and stereotypy. Pharmacol. Biochem. Behav. 2, 249–255 (1974)

    Google Scholar 

  • Smith, R. L., Dring, L. G.: Patterns of metabolism of β-phenylisopropylamines in man and other species. In: Amphetamines and related compounds; Proceedings of the Mario Negri Institute for Pharmacological Research, Milan, Italy, E. Costa and S. Garattini, eds., pp. 121–139. New York: Raven Press 1970

    Google Scholar 

  • Svensson, T. H.: Functional and biochemical effects of d-and l-amphetamine on central catecholamine neurons. Naunyn-Schmiedebergs Arch. Pharmacol. 271, 170–180 (1971a)

    Google Scholar 

  • Svensson, T. H.: The effect of inhibition of catcholamines in motor activity. M.D. thesis, Göteborgs Universitet (1971b)

  • Strömbom, U.: Catecholamine receptor agonists: effects on motor activity and rate of tyrosine hydroxylation in mouse brain. Naunyn Schmiedebergs Arch. Pharmacol. 292, 167–176 (1976)

    Google Scholar 

  • Tarsy, D., Baldessarini, R. J.: Behavioural supersensitivity to apomorphine following chronic treatment with drugs which interfere with the synaptic function of catecholamines. Neuropharmacology 13, 927–940 (1974)

    Google Scholar 

  • Ungerstedt, U.: Postsynaptic supersensitivity after 6-OH-dopamine induced degeneration of the nigro-striatal dopamine system. Acta Physiol. Scand. [Suppl.] 367, 69–93 (1971)

    Google Scholar 

  • Weissman, A., Koe, B. K., Tenen, S. S.: Antiamphetamine effects following inhibition of tyrosine hydroxylase. J. Pharmacol. Exp. Ther. 151, 339–352 (1966)

    Google Scholar 

Download references

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  1. Department of Pharmacology, University of Sydney, 2006, New South Wales, Australia

    Ruth C. Bailey & D. M. Jackson

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  1. Ruth C. Bailey
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Bailey, R.C., Jackson, D.M. A pharmacological study of changes in central nervous system receptor responsiveness after long-term dexamphetamine and apomorphine administration. Psychopharmacology 56, 317–326 (1978). https://doi.org/10.1007/BF00432856

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