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Effects ofp-chloroamphetamine on brain serotonin neurons

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Abstract

p-Chloroamphetamine (PCA) is a useful pharmacologic tool for selectively increasing brain serotonin function acutely by release of serotonin into the synaptic cleft. PCA produces behavioral, neurochemical and neuroendocrine effects believed due to serotonin release after doses in the range of 0.5–5 mg/kg. At higher doses and at longer times, PCA causes depletion of brain serotonin. The mechanisms of this depletion are not well understood but require the serotonin uptake carrier. Antagonism of PCA-induced depletion of brain serotonin is a useful means of assessing the ability of a compound to block the serotonin uptake carrier on brain serotonin neurons. PCA can also be used as a neurotoxic agent to deplete brain serotonin in functional studies, apparently by destroying some serotonergic nerve terminals. Used in this way, PCA has an advantage over 5,6- and 5,7-dihydroxytryptamines in being effective by systemic injection, and it affects brain serotonergic projections with a different neuroanatomic specificity than the dihydroxytryptamines.

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References

  1. Pletscher, A., Burkhard, W. P., Bruderer, H., and Gey, K. F. 1963. Decrease of cerebral 5-hydroxytryptamine and 5-hydroxy-indoleacetic acid by an arylalkylamine. Life Sci. 11:828–833.

    Google Scholar 

  2. Owen, J. E., Jr. 1963. Psychopharmacological studies of some 1-(chlorophenyl)-2-aminopropanes. I. Effects on appetite-controlled behavior. J. Pharm. Sci. 52:679–683.

    Google Scholar 

  3. Owen, J. E., Jr. 1963. Psychopharmacological studies of some 1-(chlorophenyl)-2-aminopropanes. II. Effects on avoidance and discrimination behavior. J. Pharm. Sci. 52:684–688.

    Google Scholar 

  4. Fuller, R. W., Hines, C. W., and Mills, J. 1964. Lowering of rat brain serotonin levels by arylalkylamines. Fed. Proc. 23:146.

    Google Scholar 

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

    Google Scholar 

  6. Sanders-Bush, E., and Sulser, F. 1970.p-Chloroamphetamine: In vivo investigations on the mechanism of action of the selective depletion of cerebral serotonin. J. Pharmacol. Exp. Ther. 175:419–426.

    Google Scholar 

  7. Sanders-Bush, E., Bushing, J. A., and Sulser, F. 1972.p-Chloroamphetamine—Inhibition of cerebral tryptophan hydroxylase. Biochem. Pharmacol. 21:1501–1510.

    Google Scholar 

  8. Sanders-Bush, E., Bushing, J. A., and Sulser, F. 1972. Long-term effects ofp-chloroamphetamine on tryptophan hydroxylase activity and on the levels of 5-hydroxytryptamine and 5-hydroxy-indoleacetic acid in brain. Eur. J. Pharmacol. 20:385–388.

    Google Scholar 

  9. Fuller, R. W., and Baker, J. C. 1977. The role of metabolic N-dealkylation in the action of p-chloroamphetamine and related drugs on brain 5-hydroxytryptamine. J. Pharm. Pharmacol. 29:561–562.

    Google Scholar 

  10. Fuller, R. W., Snoddy, H. D., and Perry, K. W. 1987.p-Chloroamphetamine formation responsible for long-term depletion of brain serotonin after N-cyclopropyl-p-chloroamphetamine injection in rats. Life Sci. 40:1921–1927.

    Google Scholar 

  11. Huang, X., Johnson, M. P., Oberlender, R., Nash, J. F., and Nichols, D. E. 1990. Acute and chronic effects of the α-ethyl homologue ofp-chloroamphetamine (PCA). Soc. Neurosci. Abstr. 16:1033.

    Google Scholar 

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

    Google Scholar 

  13. Pletscher, A., Bartholini, G., Bruderer, H., Burkhard, W. P., and Gey, K. F. 1964. Chlorinated arylalkylamines affecting the cerebral metabolism of 5-hydroxytryptamine. J. Pharmacol. Exp. Ther. 145:344–350.

    Google Scholar 

  14. Fuller, R. W., Snoddy, H. D., and Molloy, B. B. 1973. Effect of β,β-difluoro substitution on the disposition and pharmacological effects of 4-chloroamphetamine in rats. J. Pharmacol. Exp. Ther. 184:278–284.

    Google Scholar 

  15. Fuller, R. W., Snoddy, H. D., Roush, B. W., and Molloy, B. B. 1973. Further structure-activity studies on the lowering of brain 5-hydroxyindoles by 4-chloroamphetamine. Neuropharmacology 12:33–42.

    Google Scholar 

  16. Fuller, R. W., and Perry, K. W. 1983. Decreased accumulation of brain 5-hydroxytryptophan after decarboxylase inhibition in rats treated with fenfluramine, norfenfluramine orp-chloroamphetamine. J. Pharm. Pharmacol. 35:597–598.

    Google Scholar 

  17. Gallagher, D. W., and Sanders-Bush, E. 1973. In vivo measurement of the release of 5-hydroxytryptamine (5HT) from the hippocampus of the rat: effect of Ro 4-1284, pargyline andp-chloroamphetamine (PCA). Fed. Proc. 32:303.

    Google Scholar 

  18. Marsden, C. A., Conti, J., Strope, E., Curzon, G., and Adams, R. N. 1979. Monitoring 5-hydroxytryptamine release in the brain of the freely moving unanaesthetized rat using in vivo voltammetry. Brain Res. 171:85–99.

    Google Scholar 

  19. Blier, P., Serrano, A., and Scatton, B. 1990. Differential responsiveness of the rat dorsal and median raphe 5-HT systems to 5-HT1-receptor agonists and p-chloroamphetamine. Synapse 5:120–133.

    Google Scholar 

  20. Hutson, P. H., and Curzon, G. 1989. Concurrent determination of effects ofp-chloroamphetamine on central extracellular 5-hydroxytryptamine concentration and behaviour. Brit. J. Pharmacol. 96:801–806.

    Google Scholar 

  21. Adell, A., Sarna, G. W., Hutson, P. H., and Curzon, G. 1989. An in vivo dialysis and behavioural study of the release of 5-HT byp-chloroamphetamine in reserpine-treated rats. Brit. J. Pharmacol. 97:206–212.

    Google Scholar 

  22. Growdon, J. H. 1977. Postural changes, tremor, and myoclonus in the rat immediately following injections ofp-chloroamphetamine. Neurology 27:1074–1077.

    Google Scholar 

  23. Trulson, M. E., and Jacobs, B. L. 1976. Behavioral evidence for the rapid release of CNS serotonin by PCA and fenfluramine. Eur. J. Pharmacol. 36:149–154.

    Google Scholar 

  24. Davis, M., and Sheard, M. H. 1976.p-Chloroamphetamine (PCA): Acute and chronic effects on habituation and sensitization of the acoustic startle response in rats. Eur. J. Pharmacol. 35:261–273.

    Google Scholar 

  25. Zemlan, F. P., Trulson, M. E., Howell, R., and Hoebel, B. G. 1977. Influence ofp-chloroamphetamine on female sexual reflexes and brain monoamine levels. Brain Res. 123:347–356.

    Google Scholar 

  26. Orikasa, S., and Sloley, B. D. 1988. Effects of 5,7-dihydroxytryptamine and 6-hydroxydopamine on head-twitch response induced by serotonin,p-chloroamphetamine, and tryptamine in mice. Psychopharmacology 95:124–131.

    Google Scholar 

  27. Fuller, R. W., and Snoddy, H. D. 1980. Effect of serotonin-releasing drugs on serum corticosterone concentration in rats. Neuroendocrinology 31:96–100.

    Google Scholar 

  28. Fuller, R. W., Snoddy, H. D., and Clemens, J. A. 1980. Elevation of serum prolactin acutely after administration ofp-chloroamphetamine in rats. Endocr. Res. Commun. 7:77–85.

    Google Scholar 

  29. Van de Kar, L. D., Wilkinson, C. W., and Ganong, W. F. 1981. Pharmacological evidence for a role of brain serotonin in the maintenance of plasma renin activity in unanesthetized rats. J. Pharmacol. Exp. Ther. 219:85–90.

    Google Scholar 

  30. Frey, H.-H. 1970.p-Chloroamphetamine — similarities and dissimilarities to amphetamine. Pages 343–347,in Costa, E. and Garattini, S. (eds.), Amphetamines and Related Compounds, Raven Press, New York.

    Google Scholar 

  31. Fuller, R. W., and Molloy, B. B. 1974. Recent studies with 4-chloroamphetamine and some analogues. Adv. Biochem. Psychopharmacol. 10:195–205.

    Google Scholar 

  32. Sanders-Bush, E., and Steranka, L. R. 1978. Immediate and long-term effects ofp-chloroamphetamine on brain amines. Ann. N. Y. Acad. Sci. 305:208–221.

    Google Scholar 

  33. Hashimoto, K., and Goromaru, T. 1990. High-affinity [3H]6-nitroquipazine binding sites in rat brain. Eur. J. Pharmacol. 180:273–281.

    Google Scholar 

  34. Mamounas, L. A., and Molliver, M. E. 1988. Evidence for dual serotonergic projections to neocortex: axons from the dorsal and median raphe nuclei are differentially vulnerable to the neurotoxinp-chloroamphetamine (PCA). Exp. Neurol. 102:23–36.

    Google Scholar 

  35. Commins, D. L., Axt, K. J., Vosmer, G., and Seiden, L. S. 1987. Endogenously produced 5,6-dihydroxytryptamine may mediate the neurotoxic effects of para-chloroamphetamine. Brain Res. 419:253–261.

    Google Scholar 

  36. Fritschy, J. M., Lyons, W. E., Molliver, M. E., and Grzanna, R. 1988. Neurotoxic effects ofp-chloroamphetamine on the serotonergic innervation of the trigeminal motor nucleus: a retrograde transport study. Brain Res. 473:261–270.

    Google Scholar 

  37. Meek, J. L., Fuxe, K., and Carlsson, A. 1971. Blockade ofp-chloroamphetamine induced 5-hydroxytryptamine depletion by chlorimipramine, chlorpheniramine and meperidine. Biochem. Pharmacol. 20:707–709.

    Google Scholar 

  38. Fuller, R. W. 1980. Mechanism by which uptake inhibitors antagonizep-chloroamphetamine-induced depletion of brain serotonin. Neurochem. Res. 5:241–245.

    Google Scholar 

  39. Fuller, R. W., Perry, K. W., and Molloy, B. B. 1975. Reversible and irreversible phases of serotonin depletion by 4-chloroamphetamine. Eur. J. Pharmacol 33:119–124.

    Google Scholar 

  40. Fuller, R. W., Snoddy, H. D., Perry, K. W., Bymaster, F. P., and Wong, D. T. 1978. Importance of duration of drug action in the antagonism ofp-chloroamphetamine depletion of brain serotonin—comparison of fluoxetine and chlorimipramine. Biochem. Pharmacol. 27:193–198.

    Google Scholar 

  41. Berger, U. V., Grzanna, R., and Molliver, M. E. 1989. Depletion of serotonin usingp-chloroamphetamine (PCA) in the brain. Exp. Neurol. 103:111–115.

    Google Scholar 

  42. Axt, K. J., and Seiden, L. S. 1990. α-Methyl-p-tyrosine partially attenuatesp-chloroamphetamine-induced 5-hydroxytryptamine depletions in the rat brain. Pharmacol. Biochem. Behav. 35:996–997.

    Google Scholar 

  43. Sharp, T., Zetterstrom, T., Christmanson, L., and Ungerstedt, U. 1986.p-Chloroamphetamine releases both serotonin and dopamine into rat brain dialysates in vivo. Neurosci. Lett. 72:320–324.

    Google Scholar 

  44. Steranka, L. R., and Rhind, A. W. 1987. Effect of cysteine on the persistent depletion of brain monoamines by amphetamine,p-chloroamphetamine and MPTP. Eur. J. Pharmacol. 133:191–197.

    Google Scholar 

  45. Invernizzi, R., Fracasso, C., Caccia, S. Di Clemente, A., Garattini, S., and Samanin, R. 1989. Effect of L-cysteine on the long-term depletion of brain indoles caused byp-chloroamphetamine and d-fenfluramine in rats. Relation to brain drug concentrations. Eur. J. Pharmacol. 163:77–83.

    Google Scholar 

  46. Steranka, L. R., and Sanders-Bush, E. 1978. Long-term effects on continuous exposure top-chloroamphetamine: effects of inducers and inhibitors of drug metabolism. J. Pharmacol. Exp. Ther. 206:460–467.

    Google Scholar 

  47. Fuller, R. W., Perry, K. W., Baker, J. C., Parli, C. J., Lee, N., Day, W. A., and Molloy, B. B. 1974. Comparison of the oxime and the hydroxylamine derivatives of 4-chloroamphetamine as depletors of brain 5-hydroxyindoles. Biochem. Pharmacol. 23:3267–3272.

    Google Scholar 

  48. Miller, K. J., Anderholm, D. C., and Ames, M. M. 1986. Metabolic activation of the serotonergic neurotoxin para-chloroamphetamine to chemically reactive intermediates by hepatic and brain microsomal preparations. Biochem. Pharmacol. 35:1737–1742.

    Google Scholar 

  49. Berger, U. V., Molliver, M. E., and Grzanna, R. 1990. Unlike systemic administration ofp-chloroamphetamine, direct intracerebral injection does not produce degeneration of 5-HT axons. Exp. Neurol. 109:257–268.

    Google Scholar 

  50. Vorhees, C. V., Schaefer, G. J., and Barrett, R. J. 1975.p-Chloroamphetamine: behavioral effects of reduced cerebral serotonin in rats. Pharmacol. Biochem. Behav. 3:279–284.

    Google Scholar 

  51. Grabowska, M., and Michaluk, J. 1974. On the role of serotonin in apomorphine-induced locomotor stimulation in rats. Pharmacol. Biochem. Behav. 2:263–266.

    Google Scholar 

  52. Ogren, S.-O., Kohler, C., Ross, S. G., and Srebro, B. 1976. 5-Hydroxytryptamine depletion and avoidance acquisition in the rat. Antagonism of the long-term effects ofp-chloroamphetamine with a selective inhibitor of 5-hydroxytryptamine uptake. Neurosci. Lett. 3:341–347.

    Google Scholar 

  53. Altman, H. J., Ogren, S. O., Berman, R. F., and Normile, H. J. 1989. The effects ofp-chloroamphetamine, a depletor of brain serotonin, on the performance of rats in two types of positively reinforced complex spatial discrimination tasks. Behav. Neural Biol. 52:131–144.

    Google Scholar 

  54. Gob, R., Kollner, U., Kollner, O., and Klingberg, F. 1987. Early postnatal development of open field behaviour is changed by single doses of fenfluramine orp-chloroamphetamine. Biomed. Biochim. Acta 46:189–198.

    Google Scholar 

  55. Kollner, O., Kollner, U., Gob, R., and Klingberg, F. 1987. Postnatal application ofp-chloroamphetamine or fenfluramine reduces response selection during early ontogenetic development of rat avoidance behaviour. Biomed. Biochim. Acta 47:997–1005.

    Google Scholar 

  56. Nabeshima, T., Yamaguchi, K., Ishikawa, K., Furukawa, H., and Kameyama, T. 1989. Potentiation of phencyclidine and serotonin agonist-induced behaviors after administration ofp-chloroamphetamine in rats. Res. Commun. Subst. Abuse 10:37–51.

    Google Scholar 

  57. Nabeshima, T., Yamaguchi, K., Ishikawa, K., Furukawa, H., and Kameyama, T. 1987. Potentiation in phencyclidine-induced serotonin-mediated behaviors after intracerebroventricular administration of 5,7-dihydroxytryptamine in rats. J. Pharmacol. Exp. Ther. 243:1139–1146.

    Google Scholar 

  58. Hunskaar, S., Berge, O. G., Broch, O. J., and Hole, K. 1986. Lesions of the ascending serotonergic pathways and antinociceptive effects after systemic administration ofp-chloroamphetamine in mice. Pharmacol. Biochem. Behav. 24:709–714.

    Google Scholar 

  59. Kutscher, C. L., and Yamamoto, B. K. 1979. A frequency analysis of behavior components of the serotonin syndrome produced byp-chloroamphetamine. Pharmacol. Biochem. Behav. 11:611–616.

    Google Scholar 

  60. Marsden, C. A. 1979. Long term effects ofp-chloroamphetamine on hippocampal 5-hydroxytryptamine release. Brit. J. Pharmacol. 66:120P.

    Google Scholar 

  61. Archer, T., Ogren, S.-O., and Ross, S. B. 1982. Serotonin involvement in aversive conditioning: reversal of the fear retention deficit by long-termp-chloroamphetamine but notp-chlorophenylalanine. Neurosci. Lett. 34:75–82.

    Google Scholar 

  62. Fuller, R. W. 1978. Neurochemical effects of serotonin neurotoxins: An introduction. Ann. N. Y. Acad. Sci. 305:178–181.

    Google Scholar 

  63. Sanders-Bush, E., Bushing, J. A., and Sulser, F. 1975. Long-term effects ofp-chloroamphetamine and related drugs on central serotonergic mechanisms. J. Pharmacol. Exp. Ther. 192:33–41.

    Google Scholar 

  64. Alesci, R., and Bagnoli, P. 1988. Endogenous levels of serotonin and 5-hydroxyindoleacetic acid in specific areas of the pigeon CNS: effects of serotonin neurotoxins. Brain Res. 450:259–271.

    Google Scholar 

  65. Bjorkum, A. A., and Berge, O. G. 1988. The relative contribution of ascending and descending pathways inp-chloroamphetamine-induced antinociception. Pharmacol. Biochem. Behav. 31:135–140.

    Google Scholar 

  66. Perrone, M. H., Luttinger, D., Hamel, L. T., Fritz, P. M., Ferraino, R., and Haubrich, D. R. 1990. In vivo assessment of napamezole, an alpha-2 adrenoceptor antagonist and monoamine reuptake inhibitor. J. Pharmacol. Exp. Ther. 254:476–483.

    Google Scholar 

  67. Thomas, D. R., Nelson, D. R., and Johnson, A. M. 1987. Biochemical effects of the antidepressant paroxetine, a specific 5-hydroxytryptamine uptake inhibitor. Psychopharmacology 93:193–200.

    Google Scholar 

  68. Steranka, L. R., and Sanders-Bush, E. 1978. Long-term effects of continuous exposure top-chloroamphetamine on central serotonergic mechanisms in mice. Biochem. Pharmacol. 27:2033–2037.

    Google Scholar 

  69. Eide, P. K., Hole, K., Berge, O. G., and Broch, O. J. 1988. 5-HT depletion with 5,7-DHT, PCA and PCPA in mice: differential effects on the sensitivity to 5-MeODMT, 8-OH-DPAT and 5-HTP as measured by two nociceptive tests. Brain Res. 440:42–52.

    Google Scholar 

  70. Hunskaar, S., Fasmer, O. B., Broch, O. J., and Hole, K. 1987. Involvement of central serotonergic pathways in nefopam-induced antinociception. Eur. J. Pharmacol. 138:77–82.

    Google Scholar 

  71. Heinsbroek, R. P., Feenstra, M. G., Boon, P., Van Haaren, F., and Van de Poll, N. E. 1988. Sex differences in passive avoidance depend on the integrity of the central serotonergic system. Pharmacol. Biochem. Behav. 31:499–503.

    Google Scholar 

  72. Yamaguchi, K., Nabeshima, T., and Kameyama, T. 1986. Potentiation of phencyclidine-induced dopamine-dependent behaviors in rats after pretreatments with serotonin-depletors. J. Pharmacobiodyn. 9:479–489.

    Google Scholar 

  73. Rowland, D., Steele, M., and Moltz, H. 1978. Serotonergic mediation of the suckling-induced release of prolactin in the lactating rat. Neuroendocrinology 26:8–14.

    Google Scholar 

  74. Gazzara, R. A., Takeda, H., Cho, A. K., and Howard, S. G. 1989. Inhibition of dopamine release by methylenedioxymethamphetamine is mediated by serotonin. Eur. J. Pharmacol. 168:209–217.

    Google Scholar 

  75. Dilsaver, S. C., Normile, H. J., and Altman, H. J. 1989. Potentiation of oxotremorine-induced hypothermia by alaproclate in PCA lesioned and non-lesioned rats. Psychopharmacology 97:51–53.

    Google Scholar 

  76. Freo, U., Larson, D. M., Tolliver, T., Rapoport, S. I., and Soncrant, T. T. 1991. Parachloroamphetamine selectively alters regional cerebral metabolic responses to the serotonin agonist metachlorophenylpiperazine in rats. Brain Res. 544:17–25.

    Google Scholar 

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  1. Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, 46285, Indianapolis, Indiana

    Ray W. Fuller

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Special issue dedicated to Dr. Morris H. Aprison.

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Fuller, R.W. Effects ofp-chloroamphetamine on brain serotonin neurons. Neurochem Res 17, 449–456 (1992). https://doi.org/10.1007/BF00969891

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