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Thyrotropin releasing hormone: Neurochemical evidence for the potentiation of imipramine effects on the metabolism and uptake of brain catecholamines

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Abstract

The effects of chronic exposure to imipramine and thyrotropin-releasing hormone, alone and in combination, have been investigated on tyrosine hydroxylase activity as well as on the levels of norepinephrine, dopamine, and their respective metabolites in certain areas of rat brain. Repeated injections of thyrotropinreleasing hormone (20 mg/kg/24h, in two equally divided doses) for 10 days increased catecholamine synthesis and release, as shown by the increased activity of tyrosine hydroxylase and the enhanced levels of metabolites, homovanillic acid, and 4-hydroxy-3-methoxyphenylglycol. Chronic thyrotropin-releasing hormone treatment altered neither the steady state levels of norepinephrine in several brain areas, nor the uptake of 3H-norepinephrine in a crude synaptosomal (P2 pellet) fraction. By contrast, daily administration of imipramine (10 mg/kg) for 10 days significantly decreased the uptake of 3H-norepinephrine in P2 pellets by 27%. Whereas the levels of brain norepinephrine and dopamine were decreased, the concentrations of homovanillic acid and 4-hydroxy-3-methoxyphenylglycol were elevated after imipramine treatment. Furthermore, chronic imipramine treatment decreased the activity of striatal tyrosine hydroxylase, probably by receptor-mediated negative feedback mechanism. When thyrotropin-releasing hormone was injected concurrently with imipramine (10 mg/kg), this tripeptide significantly potentiated the effects of imipramine on the levels of homovanillic acid and 4-hydroxy-3-methoxyphenylglycol. These findings demonstrate that whereas thyrotropin-releasing hormone elicits its rapid mood-elevating effect probably by increasing the turnover of catecholamines, imipramine acts by blocking their neuronl re-uptake. In addition, our data provide a possible neurochemical basis for the reported potentiation of tricyclic antidepressant action by thyrotropin-releasing hormone in depressed patients.

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References

  1. Agarwal RA, Rastogi RB, Singhal RL (1977) Enhancement of locomotor activity and catecholamine and 5-hydroxytryptamine metabolism by thyrotropin releasing hormone. Neuroendocrinology 23:236–247

  2. Beley A, Beley P, Bralet J (1975) Influence de l'hypo- et de l'hyperthyroidie sur le taux de renouvellement de la noradrenaline, de la dopamine et de la serotonine dans differences structures cerebrales du rat. Arch Int Physiol Biochem 83:471–480

  3. Breese GR, Cooper BR, Prange AJ Jr, Cott JM, Lipton MA (1974) Interactions of thyrotropin-releasing hormone with centrally acting drugs. In: Prange AJ Jr (ed) The thyroid axis, drugs, and behaviour. Raven Press, New York, p 115

  4. Breese GR, Traylor TD, Prange AJ Jr (1972) The effect of triiodothyronine on the disposition and actions of imipramine. Psychopharmacology 25:101–111

  5. Brown TCK, Dwyner ME, Stocks JG (1971) Antidepressant overdosage in children — a new menace. Med J Aust 2:848–851

  6. Constantinides J, Gaillard JM, Hovaguimian T, Tissot R (1974) Enhancement of cerebral noradrenaline turnover by thyrotropin-releasing hormone: Evidence by fluorescence histochemistry. Experientia 30:1182–1184

  7. Dunner EL, Cohn CK, Gershon ES, Goodwin FK (1971) Differential catechol-O-methyl transferase activity in unipolar and bipolar affective illness. Arch Gen Psychiat 25:348–354

  8. Engstrom G, Strombom U, Svensson TH, Waldeck B (1975) Brain monoamine synthesis and receptor sensitivity after single or repeated administration of thyroxine. J Neural Transmission 37:1–10

  9. Fischetti B (1962) Pharmacological influences on thyroid activity. Arch Ital Sci Farmacol 12:33–109

  10. Garbutt J, Malekpouv B, Brunswick D, Jonnalagadda MR, Jolliff S, Podolak R, Wilson J, Prange AJ Jr (1979) Effects of triiodothyronine on drug levels and cardiac function in depressed patients treated with imipramine. Am J Psychiat 136:980–982

  11. Gershon S, Baldessarini RJ, Weeler SC (1974) Biochemical effects of dihydroxylated tryptamines on central indoleamine neurons. Neuropharmacology 13:987–1004

  12. Green AR, Heal DJ, Grahame-Smith DG (1976) The contrasting actions of TRH and cycloheximide in altering the effects of centrally acting drugs: Evidence for the non-involvement of dopamine sensitive adenylate cyclase. Neuropharmacology 15:591–599

  13. Hartmann E (1968) The effect of four drugs on sleep patterns in man. Psychopharmacologia 12:346–353

  14. Heal DJ, Green AR (1979) Administration of thyrotropin releasing hormone to rats releases dopamine in N. accumbens but not N. Caudatus. Neuropharmacology 18:23–31

  15. Jarrott B (1971) Occurance and properties of catechol-O-methyl transferase in adrenergic neurons. J Neurochem 18:17–24

  16. Keller HH, Bartholini G, Pletscher A (1974) Enhancement of cerebral noradrenaline turnover by thyrotropin-releasing hormone. Nature 248:528–529

  17. Koranyi L, Tamasy V, Lissak K, Kiraly I, Borsy J (1976) Effect of thyrotropin-releasing hormone and antidepressant agents on brainstem and hypothalamic multiple unit activity in the cat. Psychopharmacology 49:197–200

  18. Kulig BM (1975) The effect of thyrotropin-releasing hormone on the behaviour of rats pretreated with α-methyltyrosine. Neuropharmacol 14:489–492

  19. Leonard BE, Kafoe WF (1976) A comparison of the acute and chronic effects of four antidepressant drugs on the turnover of serotonin, dopamine and noradrenaline in the rat brain. Biochem. Pharmacol 25:1939–1942

  20. Loosen PT, Prange AJ Jr, Wilson IC (1979) TRH in depressed alcoholic men. Arch Gen Psychiat 36:540–547

  21. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

  22. Marek K, Hanbrick DR (1977) Thyrotropin releasin hormone-increased catabolism of catecholamines in brains of thyroidectomized rats. Biochem Pharmacol 26:1817–1818

  23. McGeer EG, Gibson S, McGeer PL (1967) Some characteristics of brain tyrosine hydroxylase. Can J Biochem 45:1557–1563

  24. Meek JL (1972) Fluorometric estimation of 4-hydroxy-3-methoxyphenylethylene-glycol sulphate in brain. Br J Pharmacol 45:435–441

  25. Miyamoto M, Nagawa Y (1977) Mesolimbic involvement in the locomotor stimulant action of thyrotropin-releasing hormone (TRH) in rats. Eur J Pharmacol 44:143–152

  26. Murphy GF, Robinson D, Sharman DF (1969) The effect of tropolone on the formation of 3,4-dihydroxyphenylacetic acid and 4-hydroxy-3-methoxyphenylacetic acid in the brain of the mouse. Br J Pharmacol 36:107–115

  27. Nielsen M, Breastrup C (1977) Despramine and some other antidepressant drugs decrease the major norepinephrine metabolite, 3,4-dihydrixyphenylglycol sulfate in the rat brain. Naunyn-Schmiedeberg's. Arch Pharmacol 300:93–99

  28. Nielsen M, Eplov L, Scheel-Kruger J (1975) The effect of amitriptyline, desipramine and imipramine on the in vivo brain synthesis of 3H-nordrenaline from 3H-l-DOPA in the rat. Psychopharmacology 41:249–254

  29. Plotnikoff NP, Kastin AJ (1976) Neuropharmacology of hypothalamic releasing factors. Biochem Pharmacol 25:363–365

  30. Prange AJ Jr, Nemeroff CB, Lipton MA, Breese GR, Wilson IC (1978) Peptides and the central nervous system. In: Iversen IL, Iversen SD, Snyder SH (eds) Handbook of pharmacology, Plenum, New York, p 1

  31. Prange AJ Jr, Wilson JC (1972) Thyrotropin releasing hormone for the immediate relief of depression: A preliminary report. Psychopharmacologia 26:82–87

  32. Prange AJ Jr, Wilson IC, Knox A, McClane TK, Lipton MA (1970) Enhancement of imipramine by thyroid stimulating hormone; Clinical and theoretical implications. Am J Psychiat 217:191–199

  33. Prange AJ Jr, Wilson IC, Rabon AM, Lipton MA (1968) Enhancement of imipramine by triiodothyronine in unselected depressed patients. Ex Med Int Congr 180:532–535

  34. Prange AJ Jr, Wilson IC, Rabon AM, Lipton MA (1969) Enhancement of imipramine antidepressant activity by thyroid hormone. Am J Psychiat 126:457–471

  35. Rastogi RB (1979) Involvement of brain aminergic systems in the pharmacology of TRH. In: Collu R, Barbeau A, Ducharme JR, Rochefort JG (eds) Central nervous system effects of hypothalamic hormones and related peptides. Raven, New York, p 123

  36. Rastogi RB, Agarwal RA, Lapierre YD, Singhal RL (1977) Effects of acute diazepam and clobazam on spontaneous locomotor activity and central amine metabolism in rats. Eur J Pharmacol 43:91–98

  37. Rastogi RB, Lapierre YD, Singhal RL (1978) Synaptosomal uptake of norepinephrine and 5-hydroxytryptamine and synthesis of catecholamines during benzodiazepine treatment. Can J Physiol Pharmacol 56:777–784

  38. Rastogi RB, Singhal RL (1976) Influence of neohatal and adult hyperthyroidism on behaviour and biosynthetic capacity for norepinephrine, dopamine and 5-hydroxytryptamine in rat brain. J Pharmacol Expt Ther 198:609–618

  39. Reigle TG, Avni J, Platz PA, Schildkraut JJ, Plotnikoff NP (1974) Norepinephrine metabolism in the rat brain following acute and chronic administration of thyrotropin-releasing hormone. Psychopharmacologia 37:1–6

  40. Roffman M, Kling MA, Cassens G, Orsulak PJ, Reigle TG, Schildkraut JJ (1977) The effects of acute and chronic administration of tricyclic antidepressants on MHPG-SO4 in rat brain. Commun Psychopharmacol 1:195–206

  41. Sacks MH, Bonforte RJ, Lasser RP, Dimich I (1968) Cardiovascular complications of imipramine intoxication. J Am Med Assoc 205:588–590

  42. Schildkraut JJ (1975) Norepinephrine metabolism after short-and long-term administration of tricyclic antidepressant drugs and electroconvulsive shock. In: Mandell AJ (ed) Neurobiological mechanisms of adaptation and behavior, Raven, New York, p 137

  43. Schildkraut JJ, Roffman M, Orsulak PJ (1976) Effects of short-and long-term administration of tricyclic antidepressants and lithium on norepinephrine turnover in brain. Pharmakopsychiat.-Neuropsychopharmakol 9:193–202

  44. Schildkraut JJ, Gordon EK, Durell J (1965) Catecholamine metabolism in affective disorders: I — Normetanephrine and VMA excretion in depressed patients treated with imipramine. J Psychiat Res 3:213–228

  45. Schildkraut JJ, Schanberg SM, Breese GR, Kopin IJ (1969) Effects of psychoactive drugs on the metabolism of intracisternally administered serotonin in rat brain. Biochem Pharmacol 18:1971–1978

  46. Schildkraut JJ, Winokur A, Applegate CW (1970) Norepinephrine turnover and metabolism in rat brain after long-term administration of imipramine. Science 168:867–868

  47. Schildkraut JJ, Winokur A, Draskoczy PR, Hensele JH (1971) Changes in norepinephrine turnover in the rat brain during chronic administration of imipramine and protriptyline: a possible explanation for the delay in onset of clinical antidepressant effects. Amer J Psychiat 127:1032–1039

  48. Segal DS, Kuczenski R, Mandell AJ (1974) Theoretical implications of drug-induced adaptive regulations for a biogenic amine hypothesis of affective disorders. Biol Psychiat 9:147–159

  49. Singhal RL, Rastogi RB (1979) Thyrotropin releasing hormone: Regional effects on α-methyl-para-tyrosine-induced catecholamine depletion in rat brain. Neuroendocrin Lett 1:11–17

  50. Spano PF, Neff NH (1971) Procedures for simultaneous determination of dopamine. 3-methoxy-4-hydroxyphenylacetic acid and 3,4-dihydroxyphenylacetic acid in the brain. Anal Biochem 42:113–118

  51. Whybrow P, Ferrell R (1974) Thyroid state and human behaviour: Contributions from a clinical perspective. In: Prange AJ Jr (ed) The thyroid axis, drugs and behaviour. Raven, New York, p 5

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Correspondence to R. L. Singhal.

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Rastogi, R.B., Singhal, R.L. & Lapierre, Y.D. Thyrotropin releasing hormone: Neurochemical evidence for the potentiation of imipramine effects on the metabolism and uptake of brain catecholamines. Psychopharmacology 72, 85–91 (1980). https://doi.org/10.1007/BF00433811

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Key words

  • Thyrotropin-releasing hormone
  • Imipramine
  • Catecholamines
  • Homovanillic acid
  • 4-Hydroxy-3-methoxyphenylglycol
  • 3H-norepinephrine uptake
  • Tyrosine hydroxylase