Research Article| Volume 20, ISSUE 8, P858-865, August 1985

Opposite effects of chronic imipramine treatment on brain and urine MHPG levels in the rat

  • M.L. Sedlock
    Address reprint requests to Dr. M. L. Sedlock, University of Pittsburgh, School of Pharmacy, Department of Pharmacology and Toxicology, 1100 Salk Hall, Pittsburgh, PA 15261.
    School of Pharmacy, Department of Pharmacology and Toxicology, Pittsburgh, PA, USA
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  • David J. Edwards
    University of Pittsburgh, School of Dental Medicine, Department of Pharmacology-Physiology, USA
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  • Author Footnotes
    1 We thank CIBA-Geigy for providing imipramine hydrochloride and Steven Knopf for performing the HPLC analysis.
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      Acute imipramine (IMI; 20 mg/kg, ip) in rats decreased the brain concentration of 3-methoxy-4-hydroxyphenethylene glycol (MHPG), a metabolite of norepinephrine (NE), to 85% of control 24 hr after injection. In contrast, chronic IMI (20 mg/kg, ip, daily for 14 days) significantly raised brain MHPG levels to 123% of control, while reducing brain NE levels. Urinary MHPG levels were reduced by both acute and chronic IMI treatments, to 52% and 51%, respectively. These data suggest that the brain turnover of NE is reduced after acute IMI, but is elevated after chronic treatment. Although urinary levels of MHPG changed in parallel with brain levels following an acute administration of IMI, such was not the case after chronic administration. We conclude that caution must be used in extrapolating drug-induced changes in urinary metabolite levels to brain amine function.
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        • Agren H.
        Depressive symptom patterns and urinary MHPG excretion.
        Psychiatry Res. 1982; 6: 185-196
        • Bareggi S.R.
        • Marc V.
        • Morselli P.L.
        Urinary excretion of 3-methoxy-4-hydroxyphenylglycol sulfate in rats after intraventricular injection of 6-OHDA.
        Brain Res. 1974; 75: 117-180
        • Beckmann H.
        • Goodwin F.K.
        Antidepressant response to tricyclics and urinary MHPG in unipolar patients.
        Arch Gen Psychiatry. 1975; 32: 17-21
        • Beckmann H.
        • Goodwin F.K.
        Urinary MHPG in subgroups of depressed patients and normal controls.
        Neuropsychobiology. 1980; 6: 91-100
        • Bickel M.H.
        • Weder H.J.
        Demethylation of imipramine in the rat as influenced by SKF 525-A and by different routes of administration.
        Life Sci. 1968; 7: 1223-1230
        • Blombery P.A.
        • Kopin I.J.
        • Gordon E.K.
        • Markey S.P.
        • Ebert M.H.
        Conversion of MHPG to vanillylmandelic acid.
        Arch Gen Psychiatry. 1980; 37: 1095-1098
        • Breese G.R.
        • Prange A.J.
        • Howard J.L.
        • Lipton M.A.
        • McKinney W.T.
        • Bowman R.E.
        • Bushnell P.
        3-Methoxy-4-hydroxyphenylglycol excretion and behavioural changes in rat and monkey after central sympathectomy with 6-hydroxydopamine.
        Nature (New Biol). 1972; 240: 286-287
        • Bunney Jr., W.E.
        • Davis J.M.
        Norepinephrine in depressive reactions.
        Arch Gen Psychiatry. 1965; 13: 483-494
        • Charney D.S.
        • Heninger G.R.
        • Sternberg D.E.
        • Redmond D.E.
        • Leckman J.F.
        • Maas J.W.
        • Roth R.H.
        Presynaptic adrenergic receptor sensitivity in depression: The effect of long-term desipramine treatment.
        Arch Gen Psychiatry. 1981; 38: 1334-1340
        • Charney D.S.
        • Heninger G.R.
        • Sternberg D.E.
        • Roth R.H.
        Plasma MHPG in depression: Effects of acute and chronic desipramine treatment.
        Psychiatry Res. 1981; 5: 217-229
        • Coppen A.
        • Rama Rao V.A.
        • Ruthven C.R.J.
        • Goodwin B.L.
        • Sandler M.
        Urinary 4-hydroxy-3-methoxyphenylglycol is not a predictor for clinical response to amitriptyline in depressive illness.
        Psychopharmacology. 1979; 64: 95-97
        • Daniel W.
        • Adamus A.
        • Melzacka M.
        • Szymura J.
        • Vetulani J.
        Cerebral pharmacokinetics of imipramine in rats after single and multiple dosages.
        Naunyn-Schmiedebergs Arch Pharmacol. 1981; 317: 209-213
        • DeLeon-Jones F.
        • Maas J.W.
        • Dekirmenjian H.
        • Sanchez J.
        Diagnostic subgroups of affective disorders and their urinary excretion of catecholamine metabolites.
        Am J Psychiatry. 1975; 132: 1141-1148
        • Edwards D.J.
        Possible role of octopamine and tyramine in the antihypertensive and antidepressant effects of tyrosine.
        Life Sci. 1982; 30: 1427-1434
        • Edwards D.J.
        • Rizk M.
        Conversion of 3,4-dihydroxyphenylalanine and deuterated 3,4-dihydroxyphenylalanine to alcoholic metabolites of catecholamines in rat brain.
        J Neurochem. 1981; 36: 1641-1647
        • Gaertner H.J.
        • Kreuter F.
        • Scharek G.
        • Wiatr G.
        • Breyer-Pfaff U.
        Do urinary MHPG and plasma drug levels correlate with response to amitriptyline therapy?.
        Psychopharmacology. 1982; 76: 236-239
        • Garfinkel P.E.
        • Warsh J.J.
        • Stancer H.C.
        Depression: New evidence in support of biological differentiation.
        Am J Psychiatry. 1979; 136: 535-539
        • Kopin I.J.
        Measuring turnover of neurotransmitters in human brain.
        in: Lipton M.A. DiMascio A. Killam K.F. Psychopharmacology: A Generation of Progress. Raven Press, New York1978: 933-942
        • Koslow S.H.
        • Maas J.W.
        • Bowden C.L.
        • Davis J.M.
        • Hanin I.
        • Javaid J.
        CSF and urinary biogenic amines and metabolites in depression and mania.
        Arch Gen Psychiatry. 1983; 40: 999-1010
        • Maas J.W.
        • Fawcett J.A.
        • Dekirmenjian H.
        Catecholamine metabolism, depressive illness, and drug response.
        Arch Gen Psychiatry. 1972; 26: 252-262
        • Maas J.W.
        • Dekirmenjian H.
        • Jones F.
        The identification of depressed patients who have a disorder of NE metabolism and/or disposition.
        in: Usdin E. Snyder S.H. Frontiers in Catecholamine Research. Pergamon Press, New York1973: 1091-1096
        • Nielsen M.
        • Braestrup C.
        Chronic treatment with desipramine caused a sustained decrease of 3,4-dihydroxyphenylglycol-sulphate and total 3-methoxy-4-hydroxyphenylglycol in the rat brain.
        Naunyn-Schmiedeberg Arch Pharmacol. 1977; 300: 87-92
        • Nielsen M.
        • Eplov L.
        • Scheel-Kruger J.
        The effect of amitriptyline, desipramine and imipramine on the in vivo brain synthesis of 3H-noradrenaline from 3H-l-Dopa in the rat.
        Psychopharmacologia (Berl). 1975; 41: 249-254
        • Reinhard Jr., J.F.
        • Roth R.H.
        Noradrenergic modulation of serotonin synthesis and metabolism. I. Inhibition by clonidine in vivo.
        J Pharmacol Exp Ther. 1982; 221: 541-546
        • Roffman M.
        • Kling M.A.
        • Cassens G.
        • Orsulak P.J.
        • Reigle T.G.
        • Schildkraut J.J.
        The effects of acute and chronic administration of tricyclic antidepressants on MHPG-SO4 in rat brain.
        Commun Psychopharmacol. 1977; 1: 195-206
        • Rosenbaum A.H.
        • Schatzberg A.F.
        • Maruta T.
        • Orsulak P.J.
        • Cole J.O.
        • Grab E.L.
        • Schildkraut J.J.
        MHPG as a predictor of antidepressant response to imipramine and maprotiline.
        Am J Psychiatry. 1980; 137: 1090-1092
        • Ross S.B.
        • Renyi A.L.
        Tricyclic antidepressant agents. I. Comparison of the inhibition of the uptake of 3H-noradrenaline and 14C-5-hydroxytryptamine in slices and crude synaptosome preparations of the midbrain-hypothalamus region of the rat brain.
        Acta Pharmacol Toxicol. 1975; 36: 382-394
        • Schatzberg A.F.
        • Orsulak P.J.
        • Rosenbaum A.H.
        • Maruta T.
        • Kruger E.R.
        • Cole J.O.
        • Schildkraut J.J.
        Toward a biochemical classification of depressive disorders, V: Heterogeneity of unipolar depressions.
        Am J Psychiatry. 1982; 139: 471-475
        • Schildkraut J.J.
        The catecholamine hypothesis of affective disorders: A review of supporting evidence.
        Am J Psychiatry. 1965; 122: 509-522
        • Schildkraut J.J.
        • Klerman G.L.
        • Hammond R.
        • Friend D.G.
        Excretion of 3-methoxy-4-hydroxymandelic acid (VMA) in depressed patients treated with antidepressant drugs.
        J Psychiatr Res. 1964; 2: 257-266
        • Schildkraut J.J.
        • Winokur A.
        • Draskoczy P.R.
        • Hensle J.H.
        Changes in norepinephrine turnover in rat brain during chronic administration of imipramine and protriptyline: A possible explanation for the delay in onset of clinical antidepressant effects.
        Am J Psychiatry. 1971; 127: 1032-1039
        • Schildkraut J.J.
        • Roffman M.
        • Orsulak P.J.
        • Schatzberg A.F.
        • Kling M.A.
        • Reigle Th.G.
        Effects of short- and long-term administration of tricyclic antidepressants and lithium on norepinephrine turnover in brain.
        Pharmakopsychiatrie. 1976; 9: 193-202
        • Schildkraut J.J.
        • Orsulak P.J.
        • Schatzberg A.F.
        • Gudeman J.E.
        • Cole J.O.
        • Rohde W.A.
        • Labrie R.A.
        Toward a biochemical classification of depressive disorders, I. Differences in urinary excretion of MHPG and other catecholamine metabolites in clinically defined subtypes of depressions.
        Arch Gen Psychiatry. 1978; 35: 1427-1433
        • Sedlock M.L.
        • Ravitch J.
        • Edwards D.J.
        The effect of dietary precursors on the excretion of amines and their metabolites in the rat.
        Biochem Med. 1985; (in press)
        • Spiker D.G.
        • Edwards D.
        • Hanin I.
        • Neil J.F.
        • Kupfer D.J.
        Urinary MHPG and clinical response to amitriptyline in depressed patients.
        Am J Psychiatry. 1980; 137: 1183-1187
        • Sugrue M.F.
        Changes in rat brain monoamine turnover following chronic antidepressant administration.
        Life Sci. 1980; 26: 423-429
        • Sugrue M.F.
        Some effects of chronic antidepressant treatments on rat brain monoaminergic systems.
        J Neural Transmiss. 1983; 57: 281-295
        • Svensson T.H.
        • Usdin T.
        Feedback inhibition of brain noradrenaline neurons by tricyclic antidepressants: α-receptor mediation.
        Science. 1978; 202: 1089-1091
        • Tang S.W.
        • Helmeste D.M.
        • Stancer H.C.
        Interaction of antidepressants with clonidine on rat brain total 3-methoxy-4-hydroxyphenylglycol.
        Can J Physiol Pharmacol. 1979; 57: 435-437
        • Veith R.C.
        • Bielski R.J.
        • Bloom V.
        • Fawcett J.A.
        • Narasimhachari N.
        • Friedel R.O.
        Urinary MHPG excretion and treatment with desipramine or amitriptyline: Prediction of response, effect of treatment, and methodological hazards.
        J Clin Psychopharmacol. 1983; 3: 18-27
        • Vetulani J.
        Complex action of antidepressant treatment on central adrenergic system: Possible relevance to clinical effects.
        Pharmacopsychiatria. 1984; 17: 16-21