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. 1991 Jul;103(3):1790–1794. doi: 10.1111/j.1476-5381.1991.tb09864.x

Cholecystokinin release mediated by 5-HT3 receptors in rat cerebral cortex and nucleus accumbens.

P Paudice 1, M Raiteri 1
PMCID: PMC1907821  PMID: 1933141

Abstract

1. The effects of 5-hydroxytryptamine (5-HT) on the release of cholexystokinin-like immunoreactivity (CCK-LI) were examined in synaptosomes prepared from rat cerebral cortex and nucleus accumbens and depolarized by superfusion with 15 mM KCl. 2. In both areas 5-HT, tested between 0.1 and 100 nM, increased the calcium-dependent, depolarization-evoked CCK-LI release in a concentration-related manner. The concentration-response curves did not differ significantly between the two brain areas (EC50: 0.4 +/- 0.045 nM and 0.48 +/- 0.053 nM, respectively, in cortical and n. accumbens synaptosomes; maximal effect: about 60% at 10 nM 5-HT). 3. The 5-HT1/5-HT2 receptor antagonist methiothepin (300 nM) did not affect the CCK-LI release elicited by 10 nM 5-HT. However, the effects of 10 nM 5-HT were antagonized in a concentration-dependent manner by the 5-HT3 receptor antagonists (3 alpha-tropanyl)-1H-indole-3-carboxylic acid ester (ICS 205-930; 0.1-100 nM; IC50: 3.56 +/- 0.42 nM in the cortex and 3.90 +/- 0.50 nM in the n. accumbens) and ondasetron (IC50: 8.15 +/- 0.73 nM in the cerebral cortex). 5-HT (10 nM) was also strongly antagonized by 100 nM 1 alpha H, 3 alpha 5 alpha H-tropan-3-yl-3,5-dichlorobenzoate (MDL 72222) another blocker of the 5-HT3 receptor. Moreover, the 5-HT3 receptor agonist 1-phenylbiguanide (tested in the cerebral cortex between 0.1 and 100 nM) enhanced CCK-LI release in a manner almost identical to that of 5-HT (EC50 = 0.64 +/- 0.071 nM). 4. It is concluded that 5-HT can act as a potent releaser of CCK-LI in rat cerebrocortex and nucleus accumbens through the activation of receptors of the 5-HT3 type situated on the CCK-releasing terminals. This interaction may provide a rationale for the clinical development of both 5-HT3 and CCK receptor antagonists as novel anxiolytic drugs.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Barnes J. M., Barnes N. M., Costall B., Naylor R. J., Tyers M. B. 5-HT3 receptors mediate inhibition of acetylcholine release in cortical tissue. Nature. 1989 Apr 27;338(6218):762–763. doi: 10.1038/338762a0. [DOI] [PubMed] [Google Scholar]
  2. Beinfeld M. C., Meyer D. K., Eskay R. L., Jensen R. T., Brownstein M. J. The distribution of cholecystokinin immunoreactivity in the central nervous system of the rat as determined by radioimmunoassay. Brain Res. 1981 May 11;212(1):51–57. doi: 10.1016/0006-8993(81)90031-7. [DOI] [PubMed] [Google Scholar]
  3. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
  4. Bradley P. B., Engel G., Feniuk W., Fozard J. R., Humphrey P. P., Middlemiss D. N., Mylecharane E. J., Richardson B. P., Saxena P. R. Proposals for the classification and nomenclature of functional receptors for 5-hydroxytryptamine. Neuropharmacology. 1986 Jun;25(6):563–576. doi: 10.1016/0028-3908(86)90207-8. [DOI] [PubMed] [Google Scholar]
  5. Bradwejn J., de Montigny C. Benzodiazepines antagonize cholecystokinin-induced activation of rat hippocampal neurones. Nature. 1984 Nov 22;312(5992):363–364. doi: 10.1038/312363a0. [DOI] [PubMed] [Google Scholar]
  6. Butler A., Hill J. M., Ireland S. J., Jordan C. C., Tyers M. B. Pharmacological properties of GR38032F, a novel antagonist at 5-HT3 receptors. Br J Pharmacol. 1988 Jun;94(2):397–412. doi: 10.1111/j.1476-5381.1988.tb11542.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Costall B., Domeney A. M., Naylor R. J., Tyers M. B. Effects of the 5-HT3 receptor antagonist, GR38032F, on raised dopaminergic activity in the mesolimbic system of the rat and marmoset brain. Br J Pharmacol. 1987 Dec;92(4):881–894. doi: 10.1111/j.1476-5381.1987.tb11394.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Derkach V., Surprenant A., North R. A. 5-HT3 receptors are membrane ion channels. Nature. 1989 Jun 29;339(6227):706–709. doi: 10.1038/339706a0. [DOI] [PubMed] [Google Scholar]
  9. Deupree D., Hsiao S. Cholecystokinin octapeptide increases passive avoidance latencies in rats. Physiol Behav. 1988;42(2):203–205. doi: 10.1016/0031-9384(88)90299-5. [DOI] [PubMed] [Google Scholar]
  10. Dockray G. J. Immunochemical evidence of cholecystokinin-like peptides in brain. Nature. 1976 Dec 9;264(5586):568–570. doi: 10.1038/264568a0. [DOI] [PubMed] [Google Scholar]
  11. Dumuis A., Sebben M., Bockaert J. The gastrointestinal prokinetic benzamide derivatives are agonists at the non-classical 5-HT receptor (5-HT4) positively coupled to adenylate cyclase in neurons. Naunyn Schmiedebergs Arch Pharmacol. 1989 Oct;340(4):403–410. doi: 10.1007/BF00167041. [DOI] [PubMed] [Google Scholar]
  12. Emson P. C., Lee C. M., Rehfeld J. F. Cholecystokinin octapeptide: vesicular localization and calcium dependent release from rat brain in vitro. Life Sci. 1980 Jun 23;26(25):2157–2163. doi: 10.1016/0024-3205(80)90603-7. [DOI] [PubMed] [Google Scholar]
  13. Fozard J. R. MDL 72222: a potent and highly selective antagonist at neuronal 5-hydroxytryptamine receptors. Naunyn Schmiedebergs Arch Pharmacol. 1984 May;326(1):36–44. doi: 10.1007/BF00518776. [DOI] [PubMed] [Google Scholar]
  14. Goa K. L., Ward A. Buspirone. A preliminary review of its pharmacological properties and therapeutic efficacy as an anxiolytic. Drugs. 1986 Aug;32(2):114–129. doi: 10.2165/00003495-198632020-00002. [DOI] [PubMed] [Google Scholar]
  15. Hughes J., Boden P., Costall B., Domeney A., Kelly E., Horwell D. C., Hunter J. C., Pinnock R. D., Woodruff G. N. Development of a class of selective cholecystokinin type B receptor antagonists having potent anxiolytic activity. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6728–6732. doi: 10.1073/pnas.87.17.6728. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Innis R. B., Snyder S. H. Distinct cholecystokinin receptors in brain and pancreas. Proc Natl Acad Sci U S A. 1980 Nov;77(11):6917–6921. doi: 10.1073/pnas.77.11.6917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Ireland S. J., Tyers M. B. Pharmacological characterization of 5-hydroxytryptamine-induced depolarization of the rat isolated vagus nerve. Br J Pharmacol. 1987 Jan;90(1):229–238. doi: 10.1111/j.1476-5381.1987.tb16844.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Iversen S. D. 5-HT and anxiety. Neuropharmacology. 1984 Dec;23(12B):1553–1560. doi: 10.1016/0028-3908(84)90099-6. [DOI] [PubMed] [Google Scholar]
  19. Jones B. J., Costall B., Domeney A. M., Kelly M. E., Naylor R. J., Oakley N. R., Tyers M. B. The potential anxiolytic activity of GR38032F, a 5-HT3-receptor antagonist. Br J Pharmacol. 1988 Apr;93(4):985–993. doi: 10.1111/j.1476-5381.1988.tb11489.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kilpatrick G. J., Jones B. J., Tyers M. B. Identification and distribution of 5-HT3 receptors in rat brain using radioligand binding. Nature. 1987 Dec 24;330(6150):746–748. doi: 10.1038/330746a0. [DOI] [PubMed] [Google Scholar]
  21. Lorén I., Alumets J., Håkanson R., Sundler F. Distribution of gastrin and CCK-like peptides in rat brain. An immunocytochemical study. Histochemistry. 1979 Feb 21;59(4):249–257. doi: 10.1007/BF00689607. [DOI] [PubMed] [Google Scholar]
  22. Peroutka S. J., Hamik A. [3H]quipazine labels 5-HT3 recognition sites in rat cortical membranes. Eur J Pharmacol. 1988 Mar 29;148(2):297–299. doi: 10.1016/0014-2999(88)90579-1. [DOI] [PubMed] [Google Scholar]
  23. Pinget M., Straus E., Yalow R. S. Localization of cholecystokinin-like immunoreactivity in isolated nerve terminals. Proc Natl Acad Sci U S A. 1978 Dec;75(12):6324–6326. doi: 10.1073/pnas.75.12.6324. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Pinget M., Straus E., Yalow R. S. Release of cholecystokinin peptides from a synaptosome-enriched fraction of rat cerebral cortex. Life Sci. 1979 Jul 23;25(4):339–342. doi: 10.1016/0024-3205(79)90264-9. [DOI] [PubMed] [Google Scholar]
  25. Raiteri M., Angelini F., Levi G. A simple apparatus for studying the release of neurotransmitters from synaptosomes. Eur J Pharmacol. 1974 Mar;25(3):411–414. doi: 10.1016/0014-2999(74)90272-6. [DOI] [PubMed] [Google Scholar]
  26. Raiteri M., Bonanno G., Marchi M., Maura G. Is there a functional linkage between neurotransmitter uptake mechanisms and presynaptic receptors? J Pharmacol Exp Ther. 1984 Dec;231(3):671–677. [PubMed] [Google Scholar]
  27. Ravard S., Dourish C. T. Cholecystokinin and anxiety. Trends Pharmacol Sci. 1990 Jul;11(7):271–273. doi: 10.1016/0165-6147(90)90004-r. [DOI] [PubMed] [Google Scholar]
  28. Rehfeld J. F. Immunochemical studies on cholecystokinin. I. Development of sequence-specific radioimmunoassays for porcine triacontatriapeptide cholecystokinin. J Biol Chem. 1978 Jun 10;253(11):4016–4021. [PubMed] [Google Scholar]
  29. Richardson B. P., Engel G., Donatsch P., Stadler P. A. Identification of serotonin M-receptor subtypes and their specific blockade by a new class of drugs. Nature. 1985 Jul 11;316(6024):126–131. doi: 10.1038/316126a0. [DOI] [PubMed] [Google Scholar]
  30. Saito A., Sankaran H., Goldfine I. D., Williams J. A. Cholecystokinin receptors in the brain: characterization and distribution. Science. 1980 Jun 6;208(4448):1155–1156. doi: 10.1126/science.6246582. [DOI] [PubMed] [Google Scholar]
  31. Sprouse J. S., Aghajanian G. K. Electrophysiological responses of serotoninergic dorsal raphe neurons to 5-HT1A and 5-HT1B agonists. Synapse. 1987;1(1):3–9. doi: 10.1002/syn.890010103. [DOI] [PubMed] [Google Scholar]
  32. Vanderhaeghen J. J., Signeau J. C., Gepts W. New peptide in the vertebrate CNS reacting with antigastrin antibodies. Nature. 1975 Oct 16;257(5527):604–605. doi: 10.1038/257604a0. [DOI] [PubMed] [Google Scholar]
  33. Waeber C., Hoyer D., Palacios J. M. 5-hydroxytryptamine3 receptors in the human brain: autoradiographic visualization using [3H]ICS 205-930. Neuroscience. 1989;31(2):393–400. doi: 10.1016/0306-4522(89)90382-5. [DOI] [PubMed] [Google Scholar]
  34. de Montigny C. Cholecystokinin tetrapeptide induces panic-like attacks in healthy volunteers. Preliminary findings. Arch Gen Psychiatry. 1989 Jun;46(6):511–517. doi: 10.1001/archpsyc.1989.01810060031006. [DOI] [PubMed] [Google Scholar]

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