Abstract
Two levels of permanent central norepinephrine depletion were obtained in rats by lesioning these neurons with small quantities of intraventricularly-applied 6-hydroxydopamine, and the effects of these lesions on a variety of standard tests of activity and emotional reactivity were studied. Both lesioned groups showed altered emotional reactivity; however, only the animals with less extensive lesions were hyperactive in running wheels, showed heightened shock-elicited aggression, were hyper-responsive to handling, and had a potentiated amphetamine-activation effect. It is suggested that these exaggerated behaviors reflected the sensitization and regeneration of partially lesioned noradrenergic circuits. These data are discussed in terms of the catecholamine hypothesis of depression.
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Bhagat, B.: Effect of chronic cold stress on catecholamine levels in rat brain. Psychopharmacologia (Berl.) 16, 1–4 (1969)
Blanchard, R. J., Blanchard, D. C.: Limbic lesions and reflexive fighting. J. comp. physiol. Psychol. 66, 603–605 (1968)
Bliss, E. L., Ailiou, J., Zwanziger, J.: Metabolism of norepinephrine, serotonin, and dopamine in rat brain with stress. J. pharmacol. exp. Ther. 164, 122–134 (1968)
Bloom, F. S., Algeri, S., Groppetti, A., Revuelta, A., Costa, E.: Lesions of central norepinephrine terminals with 6-OH-dopamine: biochemistry and fine structure. Science 166, 1284–1286 (1969)
Breese, G. R., Traylor, T. D.: Effect of 6-hydroxydopamine on brain norepinephrine and dopamine: evidence for selective degeneration of catecholamine neurons. J. Pharmacol. exp. Ther. 174, 413–420 (1970)
Brodie, H., Murphy, D., Goodwin, F., Bunney, W., Jr.: Catecholamines and mania: the effect of alpha-methyl-para-tyrosine on manic behavior and catecholamine metabolism. Clin. Pharmacol. Ther. 12, 218–224 (1971)
Bunney, W. E., Jr., Davis, J. M.: Norepinephrine in depressive reactions. Arch. gen. Psychiat. 13, 483–494 (1965)
Burkard, W. P., Jalfre, M., Blum, J.: Effect of 6-hydroxy-dopamine on behaviour and cerebral amine content in rats. Experientia (Basel) 25, 1295–1296 (1969)
Carlsson, A., Fuxe, K., Hokfelt, T.: Failure of dopamine to accumulate in central noradrenaline neurons after depletion with diethyldithiocarbamate. J. Pharm. Pharmacol. 19, 481–483 (1967)
Carlsson, A., Fuxe, K., Hokfelt, T., Lindqvist, M.: Histochemical and biochemical effects of diethyldithiocarbamate on tissue catecholamine. J. Pharm. Pharmacol. 18, 60–62 (1966)
Corrodi, H., Fuxe, K., Ljungdahl, A., Ogren, S. D.: The effect of immobilization stress on the activity of central monoamine neurons. Life Sci. 7, 107–112 (1968)
Corrodi, H., Fuxe, K., Ljungdahl, A., Ogren, S. D.: Studies on the action of some psychoactive drugs on central noradrenaline neurons after inhibition of dopamine-Β-hydroxylase. Brain Res. 24, 443–450 (1970)
Dominic, J. A., Moore, K. E.: Supersensitivity to the central stimulant actions of adrenergic drugs following discontinuation of a chronic diet of alphamethyltyrosine. Psychopharmacologia (Berl.) 15, 96–101 (1969)
Dominic, J. A., Moore, K. E.: Behavior and brain contents of catecholamines in mice during chronic administration of methyldopa. Neuropharmacology 10 565–570 (1971)
Engelman, K., Horowitz, D., Jequier, E., Sjoerdsma, A.: Biochemical and pharmacologic effects of α-methyl-tyrosine in man. J. clin. Invest. 47, 577–594 (1968)
Evetts, K. D., Uretsky, N. J., Iversen, L. L., Iversen, S. D.: Effects of 6-hydroxydopamine on CNS catecholamines, spontaneous motor activity, and amphetamine induced hyperactivity in rats. Nature (Lond.) 225, 961–962 (1970)
Fleming, R. M., Clark, W. G., Fenster, E. D., Towne, J. C.: Single extraction method for the simultaneous fluorometric determination of serotonin, dopamine, and norepinephrine in brain. Analyl. Chem. 37, 692–696 (1965)
Glick, S. D., Greenstein, S., Zimmerberg, B.: Facilitation of recovery by α-methyl-tyrosine after lateral hypothalamic damage. Science 178, 640–643 (1972)
Glowinski, J., Iversen, L. L.: Regional studies of catecholamines in the rat brain. I. The disposition of (3H) norepinephrine, (3H) dopamine, and (3H) dopa in various regions of rat brain. J. Neurochem. 13, 655–669 (1966)
Goldstein, M., Nakajima, K.: The effects of disulfiram on cateoholamine levels in the brain. J. pharm. Pharmacol. 157, 96–102 (1967)
Hanson, C.: Evidence that the central action of (+)-amphetamine is mediated via catecholamines. Psychopharmacologia (Berl.) 10, 289–297 (1967)
Hedreen, J., Chalmers, J.: Neuronal degeneration in rat brain induced by 6-hydroxydopamine: a histological and biochemical study. Brain Res. 47, 1–11 (1972)
Jackson, H.: The Croonian Lectures on evolution and dissolution of the nervous system. Brit. med. J. 1884 I 591–593, 660–663, 703–707
Katzman, R., Bjorklund, A., Owman, C., Stenevi, U., West, K.: Evidence for regenerative axon sprouting of central catecholamine neurons in the rat mesencephalon following electrolytic lesions. Brain Res. 25, 579–596 (1971)
Kendell, E. R.: The classification of depressive illness. (Maudsely Monographs Nr 18) London: Oxford University Press 1968
Klerman, G. L.: Clinical research in depression. Arch. gen. Psychiat. 24, 305–319 (1971)
Lader, M. H.: Physical and physiological aspects of anxiety and depression. Brit. J. clin. Pract. 24, 55–59 (1970)
Maickel, R. P., Cox, R. H., Saillant, J., Miller, F. P. A.: A method for the determination of serotonin and norepinephrine in discrete areas of rat brain. Int. J. Pharmacol. 7, 275–281 (1968)
Merlis, J. K.: The effect of changes in the calcium content of the cerebrospinal fluid on spinal reflex activity in the dog. Amer. J. Physiol. 131, 67–72 (1940)
Nakamura, K., Thoenen, H.: Increased irritability: a permanent behavior change induced in the rat by intraventricular administration of 6-hydroxydopamine. Psychopharmacologia (Berl.) 24, 359–372 (1972)
Pellegrino, L. J., Cushman, A. J.: A sterotaxic atlas of the rat brain. New York: Appleton-Century-Crofts 1967
Randrup, A., Munkvad, I.: Role of catecholamines in the amphetamine excitatory response. Nature (Lond.) 211, 540 (1966)
Reid, W. D., Volicer, L., Smookler, H., Veaven, M. A., Brodie, B. B.: Brain amines and temperature regulation. Pharmacology 1, 329–344 (1968)
Reis, D., Fuxe, K.: Brain norepinephrine: evidence that neuronal release is essential for sham rage behavior following brainstem transection in cat. Proc. nat. Acad. Sci. (Wash.) 64, 108–112 (1969)
Richter, C. P.: Biological clocks in medicine and psychiatry. Springfield, Ill.: Ch. C. Thomas 1965
Schildkraut, J. J.: The catecholamine hypothesis of affective disorders: a review of supporting evidence. Amer. J. Psychiat. 122, 509–522 (1965)
Schildkraut, J. J., Kety, S. S.: Biogenic amines and emotion. Science 156, 21–30 (1967)
Segal, D., Sullivan, J., Kuczenski, R., Mandell, A.: Effects of long-term reserpine treatment on brain tyrosine hydroxylase and behavioral activity. Science 173, 847–849 (1971)
Simmonds, M. A., Uretsky, N. J.: Central effects of 6-hydroxy-dopamine on the body temperature of the rat. Brit. J. Pharmacol. 40, 630–638 (1970)
Smith, C. B.: Effects of d-amphetamine upon brain amine content and locomotor activity of mice. J. Pharmacol. exp. Ther. 147, 96–102 (1965)
Stein, L.: Psychopharmacological substrates of mental depression. In: S. Garattini and M. Dukes (Eds.): Proc. 1st. Int. Symp.: Antidepressant Drugs. Exerpta Medica 1967
Stolk, J. M., Rech, R. H.: Antagonism of d-amphetamine by alpha-methyl-l-tyrosine: behavioral evidence for the participation of catecholamine stores and synthesis in the amphetamine stimulant response. Neuropharmacology 9, 249–263 (1970)
Sulser, F., Owens, M., Norvich, M., Dingell, J.: The relative role of storage and synthesis of brain norepinephrine in the psychomotor stimulation evoked by amphetamine or by desipramine and tetrabenazine. Psychopharmacologia (Berl.) 12, 322–332 (1968)
Thierry, A. M., Javoy, F., Glowinski, J., Kety, S. S.: Effects of stress on the metabolism of norepinephrine, dopamine, and serotonin in the central nervous system of the rat: I. Modification of norepinephrine turnover. J. Pharmacol. exp. Ther. 163, 163–171 (1968)
Thoa, N. B., Eichelman, B., Richardson, J., Jacobowitz, D.: 6-hydroxydopa depletion of brain norepinephrine and the facilitation of aggressive behavior. Science 178, 75–77 (1972)
Ungerstedt, U.: Postsynaptic supersensitivity after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system. Acta physiol. scand., Suppl. 367, 69–93 (1971 a)
Ungerstedt, U.: Histochemical studies on the effect of intracerebral and intraventricular injections of 6-hydroxy-dopamine on monoamine neurons in the rat brain. In: T. Malmfors and H. Thoenen (Eds.): Proceedings of the 6-Hydroxy-Dopamine Symposium, pp. 101–127. Amsterdam: North Holland Publ. 1971 b
Uretsky, N. J., Iversen, L. L.: Effects of 6-hydroxydopamine on catecholamine containing neurones in the rat brain. J. Neurochem. 17, 269–278 (1970)
Uretsky, N. J., Simmonds, M. A., Iversen, L. L.: Changes in the retention and metabolism of 3H-L-norepinephrine in rat brains in vivo after 6-hydroxy-dopamine pretreatment. J. Pharmacol. exp. Ther. 176, 489–496 (1971)
Valzelli, L.: Drugs and aggressiveness. Advanc. Pharmacol. 5, 79–108 (1967)
Weiss, J. M., Stone, E. A., Harrell, N.: Coping behavior and brain norepinephrine. J. comp. physiol. Psychol. 72, 153–160 (1970)
Weissman, A., Koe, K. and Tenen, S.: Amphetamine effects following inhibition of tyrosine hydroxylase. J. pharmacol. exp. Ther. 151, 339–352 (1965)
Wender, P. H.: The minimal brain dysfunction syndrome in children. J. nerv. ment. Dis. 155, 55–71 (1972)
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These data were part of Ph. D. dissertation by C.A.S. submitted to the Department of Psychology, U.C.L.A.
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Sorenson, C.A., Ellison, G.D. Nonlinear changes in activity and emotional reactivity scores following central noradrenergic lesions in rats. Psychopharmacologia 32, 313–325 (1973). https://doi.org/10.1007/BF00429467
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DOI: https://doi.org/10.1007/BF00429467