Skip to main content
NCBI home page
Journal of Psychiatry & Neuroscience : JPN logoLink to Journal of Psychiatry & Neuroscience : JPN
. 2000 Jan;25(1):33–42.

Cholecystokinin-induced anxiety in rats: relevance of pre-experimental stress and seasonal variations.

S Kõks 1, P T Männistö 1, M Bourin 1, J Shlik 1, V Vasar 1, E Vasar 1
PMCID: PMC1407703  PMID: 10721682

Abstract

OBJECTIVE: To examine the influence of pre-experimental stress on the anxiogenic-like action of caerulein, an agonist of cholecystokinin (CCK) receptors. Differences in the anxiety levels of rats in summer and winter, and the role of CCK in these behavioural alterations, were also examined. DESIGN: Prospective animal study. INTERVENTIONS: Male Wistar rats were injected with the CCK agonist caerulein, or the CCK antagonists L-365,260 or devazepide, after being exposed to pre-experimental stress (handling and isolation). OUTCOME MEASURES: Performance in the plus-maze model of anxiety; serum levels of prolactin, thyrotropin and growth hormone; brain density and affinity of dopamine D2, serotonin 5-HT2 and CCK receptors. RESULTS: Caerulein (5 micrograms/kg, subcutaneous injection) caused the strongest action in animals brought to the experimental room immediately before the experiment and kept in isolation after the administration of caerulein. Caerulein did not cause any reduction of exploratory activity in rats made familiar with the experimental room and kept in the home-cage after the injection of the CCK agonist. The anti-exploratory action of caerulein in stressed rats was reversed by the CCK antagonist L-365,260 (100 micrograms/kg, intraperitoneal injection), demonstrating the involvement of the CCKB receptor subtype. In addition, seasonal fluctuations occur in the exploratory activity of rats; such activity was much lower in July than in November. The rats displaying the reduced exploratory activity had an increased number of CCK receptors in the frontal cortex and hippocampus. Simultaneously, the density of serotonin 5-HT2 receptors in the frontal cortex, but not that of dopamine D2 receptors in the striatum, was elevated. The blood level of growth hormone was also higher in July. CONCLUSIONS: The anti-exploratory action of caerulein appears to be dependent on the pre-experimental stress of rats. Moreover, the seasonal variations of exploratory behaviour of rats are evident in the plus-maze model of anxiety. The reduced exploratory activity in summer appears to be related to the elevated density of CCK and 5-HT2 receptors in the brain.

Full text

PDF
33

Selected References

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

  1. Abelson J. L., Nesse R. M. Pentagastrin infusions in patients with panic disorder. I. Symptoms and cardiovascular responses. Biol Psychiatry. 1994 Jul 15;36(2):73–83. doi: 10.1016/0006-3223(94)91187-8. [DOI] [PubMed] [Google Scholar]
  2. Amirat Z., Brudieux R. Seasonal changes in in vivo cortisol response to ACTH and in plasma and pituitary concentrations of ACTH in a desert rodent, the sand rat (Psammomys obesus). Comp Biochem Physiol Comp Physiol. 1993 Jan;104(1):29–34. doi: 10.1016/0300-9629(93)90004-n. [DOI] [PubMed] [Google Scholar]
  3. Arborelius L., Owens M. J., Plotsky P. M., Nemeroff C. B. The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol. 1999 Jan;160(1):1–12. doi: 10.1677/joe.0.1600001. [DOI] [PubMed] [Google Scholar]
  4. Biró E., Sarnyai Z., Penke B., Szabó G., Telegdy G. Role of endogenous corticotropin-releasing factor in mediation of neuroendocrine and behavioral responses to cholecystokinin octapeptide sulfate ester in rats. Neuroendocrinology. 1993;57(2):340–345. doi: 10.1159/000126377. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. Bradwejn J., Koszycki D., Couëtoux du Tertre A., van Megen H., den Boer J., Westenberg H. The panicogenic effects of cholecystokinin-tetrapeptide are antagonized by L-365,260, a central cholecystokinin receptor antagonist, in patients with panic disorder. Arch Gen Psychiatry. 1994 Jun;51(6):486–493. doi: 10.1001/archpsyc.1994.03950060050005. [DOI] [PubMed] [Google Scholar]
  7. Bradwejn J., Koszycki D., Paradis M., Reece P., Hinton J., Sedman A. Effect of CI-988 on cholecystokinin tetrapeptide-induced panic symptoms in healthy volunteers. Biol Psychiatry. 1995 Dec 1;38(11):742–746. doi: 10.1016/0006-3223(95)00081-X. [DOI] [PubMed] [Google Scholar]
  8. Bradwejn J., Koszycki D., Shriqui C. Enhanced sensitivity to cholecystokinin tetrapeptide in panic disorder. Clinical and behavioral findings. Arch Gen Psychiatry. 1991 Jul;48(7):603–610. doi: 10.1001/archpsyc.1991.01810310021005. [DOI] [PubMed] [Google Scholar]
  9. Cameron O. G. Frequency of panic disorder in summer. Am J Psychiatry. 1989 Jan;146(1):123–123. doi: 10.1176/ajp.146.1.123a. [DOI] [PubMed] [Google Scholar]
  10. Charney D. S., Woods S. W., Goodman W. K., Heninger G. R. Serotonin function in anxiety. II. Effects of the serotonin agonist MCPP in panic disorder patients and healthy subjects. Psychopharmacology (Berl) 1987;92(1):14–24. doi: 10.1007/BF00215473. [DOI] [PubMed] [Google Scholar]
  11. Chrousos G. P., Gold P. W. The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA. 1992 Mar 4;267(9):1244–1252. [PubMed] [Google Scholar]
  12. Curtis G. C., Abelson J. L., Gold P. W. Adrenocorticotropic hormone and cortisol responses to corticotropin-releasing hormone: changes in panic disorder and effects of alprazolam treatment. Biol Psychiatry. 1997 Jan 1;41(1):76–85. doi: 10.1016/s0006-3223(95)00578-1. [DOI] [PubMed] [Google Scholar]
  13. Daugé V., Dor A., Féger J., Roques B. P. The behavioral effects of CCK8 injected into the medial nucleus accumbens are dependent on the motivational state of the rat. Eur J Pharmacol. 1989 Apr 12;163(1):25–32. doi: 10.1016/0014-2999(89)90391-9. [DOI] [PubMed] [Google Scholar]
  14. File S. E., Zangrossi H., Jr, Andrews N. Social interaction and elevated plus-maze tests: changes in release and uptake of 5-HT and GABA. Neuropharmacology. 1993 Mar;32(3):217–221. doi: 10.1016/0028-3908(93)90103-a. [DOI] [PubMed] [Google Scholar]
  15. Fossey M. D., Lydiard R. B., Ballenger J. C., Laraia M. T., Bissette G., Nemeroff C. B. Cerebrospinal fluid corticotropin-releasing factor concentrations in patients with anxiety disorders and normal comparison subjects. Biol Psychiatry. 1996 Apr 15;39(8):703–707. doi: 10.1016/0006-3223(95)00197-2. [DOI] [PubMed] [Google Scholar]
  16. Handley S. L., Mithani S. Effects of alpha-adrenoceptor agonists and antagonists in a maze-exploration model of 'fear'-motivated behaviour. Naunyn Schmiedebergs Arch Pharmacol. 1984 Aug;327(1):1–5. doi: 10.1007/BF00504983. [DOI] [PubMed] [Google Scholar]
  17. Harro J., Kiivet R. A., Lang A., Vasar E. Rats with anxious or non-anxious type of exploratory behaviour differ in their brain CCK-8 and benzodiazepine receptor characteristics. Behav Brain Res. 1990 Jun 18;39(1):63–71. doi: 10.1016/0166-4328(90)90121-t. [DOI] [PubMed] [Google Scholar]
  18. Harro J., Löfberg C., Pähkla R., Matto V., Rägo L., Oreland L., Allikmets L. Different molecular forms of cholecystokinin and CCKB receptor binding in the rat brain after chronic antidepressant treatment. Naunyn Schmiedebergs Arch Pharmacol. 1997 Jan;355(1):57–63. doi: 10.1007/pl00004918. [DOI] [PubMed] [Google Scholar]
  19. Harro J., Vasar E., Bradwejn J. CCK in animal and human research on anxiety. Trends Pharmacol Sci. 1993 Jun;14(6):244–249. doi: 10.1016/0165-6147(93)90020-k. [DOI] [PubMed] [Google Scholar]
  20. Harro J., Vasar E. Evidence that CCKB receptors mediate the regulation of exploratory behaviour in the rat. Eur J Pharmacol. 1991 Feb 14;193(3):379–381. doi: 10.1016/0014-2999(91)90156-k. [DOI] [PubMed] [Google Scholar]
  21. Jolkkonen J., Lepola U., Bissette G., Nemeroff C., Riekkinen P. CSF corticotropin-releasing factor is not affected in panic disorder. Biol Psychiatry. 1993 Jan 15;33(2):136–138. doi: 10.1016/0006-3223(93)90315-5. [DOI] [PubMed] [Google Scholar]
  22. Koszycki D., Zacharko R. M., Le Melledo J. M., Young S. N., Bradwejn J. Effect of acute tryptophan depletion on behavioral, cardiovascular, and hormonal sensitivity to cholecystokinin-tetrapeptide challenge in healthy volunteers. Biol Psychiatry. 1996 Oct 1;40(7):648–655. doi: 10.1016/0006-3223(95)00479-3. [DOI] [PubMed] [Google Scholar]
  23. Koszycki D., Zacharko R. M., Le Mellédo J. M., Bradwejn J. Behavioral, cardiovascular, and neuroendocrine profiles following CCK-4 challenge in healthy volunteers: a comparison of panickers and nonpanickers. Depress Anxiety. 1998;8(1):1–7. [PubMed] [Google Scholar]
  24. Kõks S., Vasar E., Soosaar A., Lang A., Volke V., Võikar V., Bourin M., Männistö P. T. Relation of exploratory behavior of rats in elevated plus-maze to brain receptor binding properties and serum growth hormone levels. Eur Neuropsychopharmacol. 1997 Nov;7(4):289–294. doi: 10.1016/s0924-977x(97)00034-5. [DOI] [PubMed] [Google Scholar]
  25. Lang A., Harro J., Soosaar A., Kõks S., Volke V., Oreland L., Bourin M., Vasar E., Bradwejn J., Männistö P. T. Role of N-methyl-D-aspartic acid and cholecystokinin receptors in apomorphine-induced aggressive behaviour in rats. Naunyn Schmiedebergs Arch Pharmacol. 1995 Apr;351(4):363–370. doi: 10.1007/BF00169076. [DOI] [PubMed] [Google Scholar]
  26. Lelliott P., Marks I., McNamee G., Tobeña A. Onset of panic disorder with agoraphobia. Toward an integrated model. Arch Gen Psychiatry. 1989 Nov;46(11):1000–1004. doi: 10.1001/archpsyc.1989.01810110042006. [DOI] [PubMed] [Google Scholar]
  27. Lepine J. P., Chignon J. M., Teherani M. Suicidal behavior and onset of panic disorder. Arch Gen Psychiatry. 1991 Jul;48(7):668–669. doi: 10.1001/archpsyc.1991.01810310086018. [DOI] [PubMed] [Google Scholar]
  28. Marriott P. F., Greenwood K. M., Armstrong S. M. Seasonality in panic disorder. J Affect Disord. 1994 Jun;31(2):75–80. doi: 10.1016/0165-0327(94)90110-4. [DOI] [PubMed] [Google Scholar]
  29. Männistö P. T., Lang A., Harro J., Peuranen E., Bradwejn J., Vasar E. Opposite effects mediated by CCKA and CCKB receptors in behavioural and hormonal studies in rats. Naunyn Schmiedebergs Arch Pharmacol. 1994 May;349(5):478–484. doi: 10.1007/BF00169136. [DOI] [PubMed] [Google Scholar]
  30. Pellow S., Chopin P., File S. E., Briley M. Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods. 1985 Aug;14(3):149–167. doi: 10.1016/0165-0270(85)90031-7. [DOI] [PubMed] [Google Scholar]
  31. Rodgers R. J., Cao B. J., Dalvi A., Holmes A. Animal models of anxiety: an ethological perspective. Braz J Med Biol Res. 1997 Mar;30(3):289–304. doi: 10.1590/s0100-879x1997000300002. [DOI] [PubMed] [Google Scholar]
  32. Rodgers R. J., Johnson N. J. Factor analysis of spatiotemporal and ethological measures in the murine elevated plus-maze test of anxiety. Pharmacol Biochem Behav. 1995 Oct;52(2):297–303. doi: 10.1016/0091-3057(95)00138-m. [DOI] [PubMed] [Google Scholar]
  33. Rägo L., Adojaan A., Harro J., Kiivet R. A. Correlation between exploratory activity in an elevated plus-maze and number of central and peripheral benzodiazepine binding sites. Naunyn Schmiedebergs Arch Pharmacol. 1991 Mar;343(3):301–306. doi: 10.1007/BF00251130. [DOI] [PubMed] [Google Scholar]
  34. Rägo L., Kiivet R. A., Harro J., Pold M. Behavioral differences in an elevated plus-maze: correlation between anxiety and decreased number of GABA and benzodiazepine receptors in mouse cerebral cortex. Naunyn Schmiedebergs Arch Pharmacol. 1988 Jun;337(6):675–678. doi: 10.1007/BF00175795. [DOI] [PubMed] [Google Scholar]
  35. Shlik J., Aluoja A., Vasar V., Vasar E., Podar T., Bradwejn J. Effects of citalopram treatment on behavioural, cardiovascular and neuroendocrine response to cholecystokinin tetrapeptide challenge in patients with panic disorder. J Psychiatry Neurosci. 1997 Nov;22(5):332–340. [PMC free article] [PubMed] [Google Scholar]
  36. Smith G. W., Aubry J. M., Dellu F., Contarino A., Bilezikjian L. M., Gold L. H., Chen R., Marchuk Y., Hauser C., Bentley C. A. Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development. Neuron. 1998 Jun;20(6):1093–1102. doi: 10.1016/s0896-6273(00)80491-2. [DOI] [PubMed] [Google Scholar]
  37. Smith M. A., Davidson J., Ritchie J. C., Kudler H., Lipper S., Chappell P., Nemeroff C. B. The corticotropin-releasing hormone test in patients with posttraumatic stress disorder. Biol Psychiatry. 1989 Aug;26(4):349–355. doi: 10.1016/0006-3223(89)90050-4. [DOI] [PubMed] [Google Scholar]
  38. Timpl P., Spanagel R., Sillaber I., Kresse A., Reul J. M., Stalla G. K., Blanquet V., Steckler T., Holsboer F., Wurst W. Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1. Nat Genet. 1998 Jun;19(2):162–166. doi: 10.1038/520. [DOI] [PubMed] [Google Scholar]
  39. Tuomisto J., Männistö P. Neurotransmitter regulation of anterior pituitary hormones. Pharmacol Rev. 1985 Sep;37(3):249–332. [PubMed] [Google Scholar]
  40. Vasar E., Peuranen E., Harro J., Lang A., Oreland L., Männistö P. T. Social isolation of rats increases the density of cholecystokinin receptors in the frontal cortex and abolishes the anti-exploratory effect of caerulein. Naunyn Schmiedebergs Arch Pharmacol. 1993 Jul;348(1):96–101. doi: 10.1007/BF00168543. [DOI] [PubMed] [Google Scholar]
  41. Wiertelak E. P., Maier S. F., Watkins L. R. Cholecystokinin antianalgesia: safety cues abolish morphine analgesia. Science. 1992 May 8;256(5058):830–833. doi: 10.1126/science.1589765. [DOI] [PubMed] [Google Scholar]
  42. 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]
  43. van Megen H. J., Westenberg H. G., Den Boer J. A., Kahn R. S. The panic-inducing properties of the cholecystokinin tetrapeptide CCK4 in patients with panic disorder. Eur Neuropsychopharmacol. 1996 Aug;6(3):187–194. doi: 10.1016/0924-977x(96)00018-1. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Psychiatry and Neuroscience are provided here courtesy of Canadian Medical Association

RESOURCES