Summary
Plasma catecholamine levels were determined in pithed rats during electrical stimulation of the entire sympathetic nervous system. In animals treated chronically with clorgyline (1 mg/kg daily for 21 days) the increment in plasma norepinephrine concentration during stimulation was greather than in control animals, whereas a single dose of clorgyline (2 mg/kg 2 h before pithing), which produced the same degree of inhibition of arterial MAO type A and a similar increase in arterial norepinephrine content, had no effect on the plasma norepinephrine response to stimulation. Injection of yohimbine (1 mg/kg) produced the same degree of enhancement of plasma norepinephrine response to stimulation in chronically treated and control animals, showing that the overall gain of the α2-adrenoceptor inhibitory loop in vascular sympathetic nerves was not affected. Plasma epinephrine concentration during electrical stimulation was also increased by chronic but not by acute clorgyline treatment. Chronic clorgyline treatment did not significantly affect the total systemic metabolic clearance rate of infused norepinephrine, thus the increased plasma norepinephrine response to stimulation reflects an increased release rate from sympathetic neurons.
In rats treated chronically with clorgyline, the pressor response to norepinephrine in the presence of yohimbine (0.3 mg/kg) was significantly reduced, whereas the pressor response to guanabenz was unchanged. There was also no change in the guanabenz-induced inhibition of the tachycardic response to electrical stimulation. These results show that the enhanced norepinephrine release produced by chronic clorgyline treatment leads to down-regulation of post-synaptic α1-adrenoreceptors with no change in post-synaptic α2-adrenoceptors or in cardiac presynaptic α2-adrenoreceptors, and are in agreement with an intrasynaptic location of α1-adrenoceptors and an extra-synaptic location of α2-adrenoceptors in the rat vasculature.
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References
Aston-Jones G, Foote SL, Bloom FE (1984) Anatomy and physiology of locus coeruleus neurons: functional implications. In: Ziegler MG, Lake CR (eds) Norepinephrine. Williams and Wilkins, Baltimore, pp 92–116
Bevan JA, Su C (1973) Sympathetic mechanisms in blood vessels: Nerve and muscle relationships. Ann Rev Pharmacol 13:269–286
Campbell IC, Robinson DS, Lovenberg W, Murphy DL (1979) The effects of chronic regimens of clorgyline and pargyline metabolism in the rat brain. J Neurochem 32:49–55
Cohen RM, Campbell IC, Cohen MR, Torda T, Pickar D, Siever LJ, Murphy DL (1980) Presynaptic noradrenergic regulation during depression and antidepressant drug treatment. J Psychiatr Res 3:93–105
Cohen RM, Campbell IC, Dauphin M, Tallman JF, Murphy DL (1982a) Changes in α- and β-receptor densities in rat brain as a result of treatment with monoamine oxidase inhibiting antidepressants. Neuropharmacology 21:293–298
Cohen RM, Campbell IC, Yamaguchi I, Pickar D, Kopin IJ, Murphy DL (1982b) Cardiovascular changes in response to selective monoamine oxidase inhibition in the rat. Eur J Pharmacol 80:155–160
Cohen RM, Ebstein RP, Daly JW, Murphy DL (1982c) Chronic effects of a monoamine oxidase-inhibiting antidepressant: decreases a functional α-adrenergic autoreceptors precede the decrease in norepinephrine-stimulated cyclic adenosine 3′∶5′-monophosphate systems in rat brain. J Neurosci 2:1588–1595
Crews FT, Smith CB (1978) Presynaptic alpha-receptor subsensitivity after long-term antidepressant treatment. Science 202:322–324
Docherty JR, McGrath JC (1980) A comparison of pre- and post-junctional potencies of several alpha-adrenoceptor agonists in the cardiovascular system and anococcygeus muscle of the rat. Naunyn-Schmiedeberg's Arch Pharmacol 312:107–116
Finberg JPM, Tal A (1985) Reduced peripheral presynaptic adrenoceptor sensitivity following chronic antidepressant treatment in rats. Br J Pharmacol 84:609–617
Finberg JPM, Tenne M (1982) Relationship between tyramine potentiation and selective inhibition of MAO types A and B in the rat vas deferens. Br J Pharmacol 77:13–21
Fuentes JA, Ordaz A, Neff NH (1979) Central mediation of the antihypertensive effect of pargyline in spontaneously hypertensive rats. Eur J Pharmacol 57:21–27
Haeusler G (1974) Clonidine induced inhibition of sympathetic nerve activity: no indication for a central presynaptic or indirect sympathomimetic mode of action. Naunyn-Schmiedeberg's Arch Pharmacol 286:97–111
Jarrott B (1971) Occurrence and properties of monoamine oxidase in adrenergic neurons. J Neurochem 18:7–16
Kopin IJ (1982) False neurotransmitters revisited: Their role in the hypotensive action of MAO inhibitors. In: Kamijo K, Usdin E, Nagatsu T (eds) Monoamine oxidase — basic and clinical frontiers. Excerpta Medica, Amsterdam, pp 321–327
Kopin IJ, Zukowska-Grojec Z, Bayorh MA, Goldstein DS (1984) Estimation of intrasynaptic norepinephrine concentrations at vascular neuroeffector junctions in vivo. Naunyn-Schmiedeberg's Arch Pharmacol 325:298–305
Linnoila M, Karoun F, Potter WZ (1982) Effect of low dose clorgyline on 24-hour binary monoamine excretion in patients with rapidly cycling bipolar affective disorder. Arch Gen Psychiatr 39:513–516
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275
McGrath JC (1982) Evidence for more than one type of postjunctional α-adrenoceptor. Biochem Pharmacol 31:467–484
Neff NH, Costa E (1966) The influence of monoamine oxidase inhibition on catecholamine synthesis. Life Sci 5:951–959
Pscheidt GR (1963) Anomalous actions of monoamine oxidase inhibitors. Ann NY Acad Sci 107:1057–1067
Schildkraut JJ (1965) The catecholamine hypothesis of affective disorders: A review of supporting evidence. Am J Psychiatr 122:2103–2104
Siever LJ, Uhde TW, Murphy DL (1982) Possible subsensitization of alpha2-adrenergic receptors by chronic monoamine oxidase inhibitor treatment in psychiatric patients. Psychiatr Res 6:293–302
Sigg EB, Seffer L, Gyermek L (1963) Influence of imipramine and related psychoactive agents on the effect of 5-hydroxytryptamine and catecholamines on the cat nictitating membrane. J Pharmacol Exp Ther 142:13–20
Sugrue MF (1981) Chronic antidepressant administration and adaptive changes in central monoaminergic systems. In: Enna SJ, Malick JB, Richelson E (eds) Antidepressants: neurochemical, behavioral and clinical perspectives. Raven, New York, pp 13–30
Sulser F, Vetulani J, Mobley PL (1978) Mode of action of antidepressant drugs. Biochem Pharmacol 27:257–261
Tipton K, Youdin MBH (1976) Assay of monoamine oxidase. In: Wolstenholme GEW, Knight J (eds) Monoamine oxidase and its inhibition. Elsevier, Amsterdam, pp 393–403
U'Prichard DC, Bechtel WP, Rouot BM, Snyder SH (1979) Multiple apparent α-noradrenergic receptor binding sites in rat brain: Effect of 6-hydroxydopamine. Mol Pharmacol 16:47–60
Yamaguchi I, Kopin IJ (1979) Plasma catecholamine and blood pressure responses to sympathetic stimulation in pithed rats. Am J Physiol 237:H305-H310
Yamaguchi I, Kopin IJ (1980) Blood pressure, plasma catecholamines, and sympathetic outflow in pithed SHR and WKY rats. Am J Physiol 238:365–372
Zukowska-Grojec Z, Bayorh MA, Kopin IJ (1983) Effect of desipramine on the effects of α-adrenoceptor inhibitors or pressor responses and release of norepinephrine into plasma of pithed rats. J Cardiovasc Pharmacol 5:297–301
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Finberg, J.P.M., Kopin, I.J. Chronic clorgyline treatment enhances release of norepinephrine following sympathetic stimulation in the rat. Naunyn-Schmiedeberg's Arch. Pharmacol. 332, 236–242 (1986). https://doi.org/10.1007/BF00504860
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DOI: https://doi.org/10.1007/BF00504860