Molecular Mechanisms Controlling Norepinephrine-Mediated Release of Serotonin from Rat Pineal Glands

  • Richard F. Walker
  • Vincent J. Aloyo
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 221)


This study describes various elements of the mechanism controlling norepinephrine (NE)-mediated release of serotonin (5HT) from rat pineal glands. After radiolabelling the endogenous pool of pineal 5HT with 3H-5HT, individual pineal glands were exposed to depolarizing buffers or those containing NE. Although 3H-5HT was not released by 50mM potassium, efflux of the indoleamine was increased by NE. Alpha-adrenergic receptors mediate the effects of NE as indicated by the fact that phenylephrine but not isoproterenol, a beta receptor agonist, also enhanced 3H-5HT release. This hypothesis is supported further by the fact that prazosin and phentolamine (alpha-antagonists) but not sotolal (beta-antagonist), inhibited the stimulatory effects of NE on 5HT release. In order to determine the intracellular second messenger involved in the 5HT release process, pineals were incubated with 8-bromo cAMP or the phorbol ester, PMA. PMA simulated the effects of NE and phenylephrine on 3H-5HT efflux, while cAMP had no effect. Furthermore, calcium-, phospholipid-dependent protein kinase activities in pineal homogenates were responsive to NE. These findings suggest that 5HT secretion from rat pinealocytes occurs rapidly in response to NE signals that act through alphaadrenergic receptors in concert with phospholipid dependent protein kinase(s). These molecular processes are different from those involved in melatonin metabolism and may represent a general mechanism for regulating 5HT release in the brain.


Pineal Gland Beta Receptor Agonist Phospholipid Dependent Protein Kinase Dibutyryl Adenosine Noradrenergic Signal 
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  1. Aghajanian, G. K., Rosecrans, J. A. and Sheard, M.H., Serotonin: release in the forebrain by stimulation of mid brain raphe, Science 156:402–403 (1967).CrossRefGoogle Scholar
  2. Aghajanian, G. K., Wang, R. Y. and Baraban, J., Serotonergic and non-sero-tonergic neurons of the dorsal raphe: Reciprocal changes in firing induced by peripheral nerve stimulation, Brain Res. 153:169–175 (1978).CrossRefGoogle Scholar
  3. Aloyo, V. J. and Walker, R. F., Noradrenergic control of serotonin release from rat pineal glands, in vitro, Endocrinology (In Press) (1986).Google Scholar
  4. Craft, C. M., Morgan, W. W. and Reiter, R. J., 24-hour changes in catecholamine synthesis in rat and hamster pineal glands, Neuroendocrinology 38:193–198 (1984).CrossRefGoogle Scholar
  5. Descarries, L., Beaudet, A., Watkins, K. C. and Garcia, S., The serotonin neurons in nucleus raphe dorsalis of adult rat, Anat. Rec. 193:520 (1979).Google Scholar
  6. Ducis, I. and DiStefano, V., Evidence for a serotonin uptake system in isolated bovine pinealocyte suspension, Mol. Pharm. 18:438 (1980).Google Scholar
  7. Ducis, I. and DiStefano, V., Characterization of serotonin uptake in isolated bovine pinealocyte suspension, Mol. Pharm. 18:447 (1980).Google Scholar
  8. Ebadi, M. S., Weiss, B. and Costa, E., Adenosine 3′, 5′-monophosphate in rat pineal gland: increase induced by light, Science 170:188–190 (1970).CrossRefGoogle Scholar
  9. Eichberg, J., Shein, H. M., Schwartz, M. and Hauser, G., Stimulation of 32P; incorporation into phosphatidylinositol and phosphatidylglycerol by catecholamines and β-adrenergic receptor blocking agents in rat pineal organ cultures, J. Biol. Chem. 248:3615–3622 (1973).Google Scholar
  10. Essman, W. B., Serotonin in Health and Disease. Vol. II: Physiological Regulation and Pharmacological Action, Spectrum Publication, Inc. New York (1978).Google Scholar
  11. Fontana, J. A. and Lovenberg, W., A cyclic AMP-dependent protein kinase of the bovine pineal gland, Proc. Natl. Acad. Sci. USA 68:2787–2790 (1971).CrossRefGoogle Scholar
  12. Garrick, N. A., Tamarkin, L., Taylor, P. L., Markey, S. P. and Murphy, D. L., Light and propranolol suppress the nocturnal elevation of serotonin in the cerebrospinal fluid of rhesus monkeys, Science 221:474 (1983).CrossRefGoogle Scholar
  13. Grahame-Smith, D. G., Tryptophan hydroxylation in brain, Biochem. Biophys. Res. Commun. 16:586–592 (1964).CrossRefGoogle Scholar
  14. Hansen, J. T. and Karasek, M., Neuron or Endocrine Cell? The Pinealocyte as a paraneuron, Prog. Clin. Biol. Res. 92:1–9 (1982).Google Scholar
  15. Hauser, G., Shein, H. M. and Eichberg, J., Relationship of α-adrenergic receptors on rat pineal gland to drug-induced stimulation of phospholipid metabolism, Nature 252:482–483 (1974).CrossRefGoogle Scholar
  16. Hery, F., Rouer, E. and Glowinski, J., Daily variations of serotonin metabolism in the rat brain, Br. Res. 43:445–465 (1972).CrossRefGoogle Scholar
  17. Hillier, J. G., Martin, P. R. and Redfern, P. H., A possible interaction between the 24-hour rhythms in catecholamines and 5-hydroxytryptamine concentration in the rat brain, J. Pharm. Pharmacol, (Suppl. 2) 27:40P (1975).Google Scholar
  18. Jequier, E., Robinson, D. S., Lovenberg, W. and Sjoerdsma, A., Further studies on tryptophan hydroxylase in rat brain stem and beef pineal, Biochem. Pharmacol. 18:1071–1081 (1969).CrossRefGoogle Scholar
  19. Klein, D. C., Circadian rhythms in indole metabolism in the rat pineal gland, In: C. S. Pittendrigh (Ed). Circadian Oscillations and Organization in Nervous System, MIT Press, Cambridge, pp. 509–515 (1975).Google Scholar
  20. Klein, D. C. and Weller, J. L., Indole metabolism in the pineal gland: A circadian rhythm in N-acetyltransferase, Science 169:1093–1095 (1970).CrossRefGoogle Scholar
  21. Klein, D. C. and Weller, J. L., Adrenergic-adenosine 3′, 5′-monophosphate regulation of serotonin N-acetyltransferase activity and the temporal relationship of serotonin N-acetyltransferase activity to synthesis of 3H-N-acetyl-serotonin and 3H-melatonin in cultured rat pineal gland, J. Pharmacol. Exp. Ther. 186:518–527 (1973).Google Scholar
  22. Klein, D. C., Berg, G. R. and Weller, J. L., Melatonin synthesis: adenosine 3′, 5′-monophosphate and norepinephrine stimulate N-acetyl-trans-ferase, Science, 168:979–986 (1978).CrossRefGoogle Scholar
  23. Klein, D. C., Sugden, D. and Weller, J. L., Postsynaptic α-adrenergic receptors potentiate the β-adrenergic.stimulation of pineal serotonin N-acetyltransferase, Proc. Natl. Acad. Sci. USA 80:599–603 (1983).CrossRefGoogle Scholar
  24. Klein, D. C., Weiler, J. L. and Moore, R. Y., Melatonin metabolism: neural regulation of pineal serotonin: acetyl coenzyme A N-acetyltransferase activity, Proc. Nat. Acad. Sci. 68:3107–3110 (1971).CrossRefGoogle Scholar
  25. Moore, R. Y., The innervation of the mammalian pineal gland, Prog. Reprod. Biol. 4:1–29 (1978).Google Scholar
  26. Moore, R. Y., The retinohypothalamic tract, suprachiasmatic hypothalamic nucleus and central neural mechanisms of circadian rhythm regulation, In: M. Suda, O. Hayaish and H. Nakagawa (Eds), Biological Rhythms and their Central Mechanisms, Elsevier, Amsterdam, pp. 343–354 (1979).Google Scholar
  27. Morgan, W. W. and Reiter, R. J., Pineal noradrenaline levels in the Monge-lian gerbil and in different strains of laboratory rats over a lighting regimen, Life Sci. 21:555–558 (1977).CrossRefGoogle Scholar
  28. Plaznik, A., Danysz W., Kostowki, W., Bidzinski, A. and Hauptmann, M., Interaction between noradrenergic and serotoninergic brain systems as evidenced by behavioral and biochemical effects of microinjections of adrenergic agonists and antagonists into the median raphe nucleus, Pharm. Biochem. Behav. 19:27–32 (1983).CrossRefGoogle Scholar
  29. Quay, W. B., Circadian rhythm in rat pineal serotonin and its modifications by estrous cycle and photoperiod, Gen Comp Endocrinol 3:473–479 (1963).CrossRefGoogle Scholar
  30. Quay, W. B., Circadian and estrous rhythms in pineal melatonin and 5-hydroxy-indole-3-acetic acid, Proc. Soc. Exp. Biol. Med. 115:710–713 (1964).Google Scholar
  31. Reiter, R. J., The pineal and its hormones in the control of reproduction in mammals, Endocrine Reviews 1:109–131 (1980).CrossRefGoogle Scholar
  32. Saavedra, J. M., Distribution of serotonin and synthesizing enzymes in discrete areas of the brain, Fed. Proc. 36:2134–2141 (1977).Google Scholar
  33. Shein, H. M. and Wurtman, R. J., Stimulation of 14[C] tryptophan 5-hydroxy-lation of norepinephrine and dibutyryl adenosine 3′, 5′-monophosphate on rat pineal organ cultures, Life Sciences 10:935–940 (1971).CrossRefGoogle Scholar
  34. Shibuya, H., Toru, M. and Watanabe, S., A circadian rhythm of tryptophan hydroxylase in rat pineals, Brain Res. 138:364–368 (1978).CrossRefGoogle Scholar
  35. Sitaram, B. R. and Lees, G. J., Diurnal rhythm and turnover of tryptophan hydroxylase in the pineal glands of the rat, J. Neurochem. 31:1021–1026 (1978).CrossRefGoogle Scholar
  36. Smith, T. L., Eichberg, J. and Hauser, G., Postsynaptic localization of the alpha receptor-mediated stimulation of phosphotidylinositol turnover in pineal gland, Life Sci. 24:2179–2184 (1979).CrossRefGoogle Scholar
  37. Sugden, D., Vancecek, J., Klein, D. C., Thomas, T. P. and Anderson, W. B., Activation of protein Kinase C potentiates isoproterenol induced cyclic AMP accumulation in rat pinealocytes, Nature (1985).Google Scholar
  38. Taylor, P. L., Garrick, N. A., Burns, R. S., Tamarkin, L., Murphy, D. L. and Markey, S. P., Diurnal rhythms of serotonin in monkey cerebrospinal fluid, Life Sci. 31:1993 (1982).CrossRefGoogle Scholar
  39. Taylor, P. A., Garrick, N. A., Tamarkin, L., Murphy, D. L. and Markey, S. P., Diurnal rhythms of N-acetylserotonin and serotonin in cerebrospinal fluid of monkeys, Science 228:900 (1985).CrossRefGoogle Scholar
  40. Tsang, D. and Martin, J. B., Effect of hypothalamic hormones on the concentration of adenosine 3′, 5′-monophosphate in the incubated rat pineal gland, Life Sci. 19:911–918 (1976).CrossRefGoogle Scholar
  41. Walker, R. F., Sparks, D. L., Slevin, J. and Rush, M. E., Temporal effects of norepinephrine on pineal serotonin in vitro, J. Pin. Res. 3:33–40 (1986).CrossRefGoogle Scholar
  42. Walker, R. F. and Aloyo, V. J., Norepinephrine stimulates serotonin secretion from rat pineal glands, in vitro, Br. Res. 343:188–190 (1985).CrossRefGoogle Scholar
  43. Weck, M. and Wake, K., The pinealocyte-a paraneuron. A Review, Arch. Histol. Jap. 40 (suppl)261–278 (1977).Google Scholar
  44. Wilkinson, M., Inhibition of the noradrenergic induction of pineal N-acetyl-transferase by dibutyryl cyclic guanosine monophosphate and by ionphore X-537A, Neurosci. Lett. 2:29–33 (1976).CrossRefGoogle Scholar
  45. Wilkinson, M., The sensitivity of pineal gland β-receptors appears to be dependent upon calcium ions, Pflugers Arch. 373:209–210 (1978).CrossRefGoogle Scholar
  46. Winter, K. E., Morrissey, J. J., Loos, P. J. and Lovenberg, W., Pineal protein phosphorylation during serotonin N-acetyl-transferase induction, Proc. Natl. Acad. Sci. USA 74:1928–1931 (1977).CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1987

Authors and Affiliations

  • Richard F. Walker
    • 1
    • 2
  • Vincent J. Aloyo
    • 2
  1. 1.Department of Reproductive and Developmental ToxicologySmith Kline and French LaboratoriesPhiladelphiaUSA
  2. 2.Medical College of PennsylvaniaPhiladelphiaUSA

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