TRH Interactions with Cholinergic Mechanisms and Consequent Therapeutic Implications

  • George G. Yarbrough


Subsequent to the claim that thyrotropin-releasing hormone (TRH; pyroglutamyl-histidyl-proline amide) was effective in the treatment of depression (Prange and Wilson, 1972) and the demonstration that TRH enhanced the stimulant properties of L-dopa in mice (Plotnikoff et al., 1972), a great deal of experimental work has been devoted to elucidating both the basic pharmacological properties of this small peptide and its underlying mode of action. To date, a unifying hypothesis that would satisfactorily account for the multiple and unique actions of exogenously administered TRH is not apparent. Similarly, the functional significance of endogenous, extrahypothalamic TRH, which is found in both mammalian and nonmammalian species, is largely a matter of conjecture. However, with continued research in a variety of experimental preparations an unusual property, which appears to underlie many of the pharmacological effects of TRH, has emerged; namely that TRH, at all levels of the neuraxis and in a unique fashion, appears to facilitate cholinergic transmission via a unique action on central cholinergic neurons. The evidence for these phenomena and consequent therapeutic indications are summarized below.


Choline Uptake Antimuscarinic Agent Cholinergic Mechanism Cerebral Cortical Neuron Vagal Efferents 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Atweh, S., Simon, J. R., and Kuhar, M. J., 1975, Utilization of sodium-dependent high affinity choline uptake in vitro as a measure of the activity of cholinergic neurons in vivo, Life Sci. 17:1535.PubMedCrossRefGoogle Scholar
  2. Beale, J. S., White, R. P., and Huang, S. P., 1977, EGG and blood pressure effects of TRH in rabbits, Neuropharmacology 16:499.PubMedCrossRefGoogle Scholar
  3. Braitman, D. J., Auker, C.R., and Carpenter, D. O., 1980, Thyrotropin-releasing hormone has multiple actions in cortex, Brain Res. 194:244.PubMedCrossRefGoogle Scholar
  4. Breese, G. R., Cott, J. M., Cooper, B. R., Prange, A. J., Lipton, M. A., and Plotnikoff, N. P., 1975, Effects of thyrotropin-releasing hormone on the actions of pentobarbital and other centrally active drugs, J. Pharmacol. Exp. Ther. 193:11.PubMedGoogle Scholar
  5. Briggs, I., 1979, Excitatory effects of TRH on medullary reticular neurones, Neurosci. Lett. 15:33.PubMedCrossRefGoogle Scholar
  6. Cooper, B. R., and Boyer, C. E., 1978, Stimulant action of thyrotropin releasing hormone on cat spinal cord, Neuropharmacology 17:153.PubMedCrossRefGoogle Scholar
  7. Furukawa, K., Nomoto, T., and Tonoue, T., 1980, Effects of thyrotropin-releasing hormone (TRH) on the isolated small intestine and taenia coli of the guinea pig, Eur. J. Pharmacol. 64:279.PubMedCrossRefGoogle Scholar
  8. Gascoigne, A. D., Hirst, B. H., Reed, J. D., and Shaw, B., 1980, Effects of thyrotrophin-releasing hormone, and methionine-enkephalin on gastric acid and pepsin secretion in the cat, Br. J. Pharmacol. 69:527.PubMedGoogle Scholar
  9. Horita, A., Carino, M. A., and Chesnut, R. M., 1976, Influence of thyrotropin-releasing hormone (TRH) on drug induced narcosis and hypothermia in rabbits, Psychopharmacol. Bull. 49:57.Google Scholar
  10. Kalivas, P. W., and Horita, A., 1980, Thyrotropin-releasing hormone: Neurogenesis of actions in the pentobarbital narcotized rat, J. Pharmacol. Exp. Ther. 212:203.PubMedGoogle Scholar
  11. Kalivas, P. W., Halpern, L. M., and Horita, A., 1980, Synchronization of hippocampal and cortical electroencephalogram by thyrotropin-releasing hormone, Exp. Neurol. 69:627.PubMedCrossRefGoogle Scholar
  12. Koranyi, L., Sawyer, C., and Whitmoyer, D., 1977, Effect of thyrotropin-releasing hormone, luteinizing hormone-releasing hormone, and somatostatin on neuronal activity of brain stem reticular formation and hippocampus in the female rat, Exp. Neurol. 57:807.PubMedCrossRefGoogle Scholar
  13. Koss, M. C., 1980, Stimulant action of thyrotropin-releasing hormone on ciliary nerve activity, Eur. J. Pharmacol. 65:105.PubMedCrossRefGoogle Scholar
  14. Koss, M., and Stone, C., 1980, Increase of tonic parasympathetic outflow to the pupil produced by an analog of TRH (MK-771), Regul. Peptides 1:31.CrossRefGoogle Scholar
  15. McNaughton, N., Jamus, D. T. D., Stewart, J., Gray, J. A., Valevo, I., and Drewnowski, A., 1977, Septal driving of hippocampal theta rhythm as a function of frequency in the male rat: Effects of drugs, Neuroscience 2:1019.CrossRefGoogle Scholar
  16. Malthe-Sorenssen, D., Wood, P. L., Cheney, D. L., and Costa, E., 1978, Modulation of the turnover rate of acetylcholine in rat brain by intraventricular injections of thyrotropin-releasing hormone, somatostatin, neurotensin and angiotensin II, J. Neurochem. 31:685.PubMedCrossRefGoogle Scholar
  17. Nagai, Y., Narumi, S., Nagawa, Y., Sakurada, O., Ueno, H., and Ishii, S., 1980, Effect ofthy-rotropin-releasing hormone (TRH) on local cerebral glucose utilization, by the autoradiographic 2-deoxy[14C]glucose method, in conscious and phenobarbitalized rats, J. Neurochem. 35:963.PubMedCrossRefGoogle Scholar
  18. Nicoll, R. A., 1977, Excitatory action of TRH on spinal motoneurones, Nature (London) 265:242.CrossRefGoogle Scholar
  19. Phillis, J. W. (ed.), 1970, The Pharmacology of Synapses, Pergamon Press, Elmsford, N.Y.Google Scholar
  20. Phillis, J. W., and Kirpatrick, J. R., 1979, Actions of various gastrointestinal peptides on the isolated amphibian spinal cord, Can. J. Physiol. Pharmacol. 57:887.PubMedCrossRefGoogle Scholar
  21. Phillis, J. W., and Kirkpatrick, J., 1980, The actions of motilin, luteinizing hormone releasing hormone, cholecystokinin, somatostatin, vasoactive intestinal peptide, and other peptides on rat cerebral cortical neurons, Can. J. Physiol. Pharmacol. 58:612.PubMedCrossRefGoogle Scholar
  22. Phillis, J. W., Mullin, W. J., and Pinsky, C., 1973, Morphine enhancement of acetylcholine release into the lateral ventricle and from the cerebral cortex of unanaesthetized cats, Comp. Gen. Pharmacol. 4:189.PubMedCrossRefGoogle Scholar
  23. Plotnikoff, N. P., Prange, A. J., Jr., Breese, G. R., Anderson, M. S., and Wilson, I. C., 1972, Thyrotropin-releasing hormone: Enhancement of DOPA activity by a hypothalamic hormone, Science 178:417.PubMedCrossRefGoogle Scholar
  24. Prange, A. J., and Wilson, I. C., 1972, Thyrotropin-releasing hormone (TRH) for the immediate relief of depression: A preliminary report, Psychopharmacologia 26:82.Google Scholar
  25. Renaud, L. P., and Martin, J. B., 1975, Thyrotropin-releasing hormone: Depressant action on central neuronal activity, Brain Res. 86:150.PubMedCrossRefGoogle Scholar
  26. Renaud, L. P., Blume, H. W., Pittman, Q. J., Lamour, Y., and Tan, A. T., 1979, Thyrotropin-releasing hormone selectively depresses glutamate excitation of cerebral cortical neurons, Science 205:1275.PubMedCrossRefGoogle Scholar
  27. Santori, E., and Schmidt, D., 1980, Effects of MK-771, a TRH analog, on pentobarbital-induced alterations of cholinergic parameters in discrete regions of rat brain, Regul. Peptides 1:69.CrossRefGoogle Scholar
  28. Schenkel-Hulliger, L., Koella, W. P., Hartmann, A., and Maitre, L., 1974, Tremorogenic effect of thyrotropin-releasing hormone in rats, Experientia 30:1168.PubMedCrossRefGoogle Scholar
  29. Schmidt, D. E., 1977, Effects of thyrotropin-releasing hormone (TRH) on pentobarbital-induced decrease in cholinergic neuronal activity, Commun. Psychopharmacol. 1:469.PubMedGoogle Scholar
  30. Smith, J. R., La Hann, T. R., Chestnut, R. M., Carino, M. A., and Horita, A., 1977, Thyrotropin-releasing hormone: Stimulation of colonic activity following intracerebroventricular administration, Science 196:660.PubMedCrossRefGoogle Scholar
  31. Tache, Y., Brown, M., and Vale, W., 1980, Thyrotropin-releasing hormone—CNS action to stimulate gastric acid secretion, Nature (London) 287:149.CrossRefGoogle Scholar
  32. Tonoue, T., and Nomoto, T., 1979, Effect of intracerebro ventricular administration of thyrotropin-releasing hormone upon the electroenteromyogram of rat duodenum. Eur. J. Pharmacol. 58:369.PubMedCrossRefGoogle Scholar
  33. Veber, D. F., Holly, F. W., Varga, S. L., Hirschmann, R., Nutt, R. F., Lotti, V. J., and Porter, C. C., 1976, The dissociation of hormonal and CNS effects in analogs of TRH, Proceedings 14th European Peptide Symposium (A. Loffet, ed.), pp. 167–172, University of Brunds Press, Belgium.Google Scholar
  34. Winokur, A., and Beckman, A. L., 1978, Effects of thyrotropin releasing hormone, norepinephrine and acetylcholine on the activity of neurons in the hypothalamus, septum and cerebral cortex of the rat, Brain Res. 150:205.PubMedCrossRefGoogle Scholar
  35. Yarbrough, G. G., 1978, Studies on the neuropharmacology of thyrotropin releasing hormone (TRH) and a new TRH analog, Eur. J. Pharmacol. 48:19.PubMedCrossRefGoogle Scholar
  36. Yarbrough, G. G., 1979, On the neuropharmacology of thyrotropin releasing hormone (TRH), Prog. Neurobiol. 12:291.PubMedCrossRefGoogle Scholar
  37. Yarbrough, G. G., and McGuffin-Clineschmidt, J. C., 1979, MK-771-induced electromyographic (EMG) activity in the rat: Comparison with thyrotropin releasing hormone (TRH) and antagonism by neurotensin, Eur. J. Pharmacol. 60:41.PubMedCrossRefGoogle Scholar
  38. Yarbrough, G. G., and Singh, D. K., 1979, Effects of MK-771 on the isolated amphibian spinal cord: Comparison with thyrotropin-releasing hormone, Can. J. Physiol. Pharmacol. 57(8):920.PubMedCrossRefGoogle Scholar
  39. Yarbrough, G. G., Haubrich, D. R., and Schmidt, D. E., 1978, Thyrotropin releasing hormone (TRH) and MK-771 interactions with CNS cholinergic mechanisms, in: Iontophoresis and Transmitter Mechanisms in the Mammalian Central Nervous System (R. Ryall and J. S. Kelly, eds.), pp. 136–138, Elsevier/North-Holland, Amsterdam.Google Scholar

Copyright information

© Plenum Publishing Corporation 1984

Authors and Affiliations

  • George G. Yarbrough
    • 1
  1. 1.Merck Institute for Therapeutic ResearchWest PointUSA

Personalised recommendations