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Opposite effects mediated by CCKA and CCKB receptors in behavioural and hormonal studies in rats

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Abstract

We compared the influence of two cholecystokinin (CCK) antagonists, devazepide and L,365,260 [3R-(+)-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1 H-1,4-benzodiazepine-3y1)-N′-(3-methyl-phenyl)urea], upon two distinct phenomena, behavioural and hormonal effects of caerulein (5 μg/kg s.c.), and unselective CCK agonist, in rats. Behavioural effects were assessed in the elevated plusmaze and open field tests. In separate experiments, effects on thyrotropin (TSH), prolactin (PRL) and growth hormone (GH) levels in serum of male rats were studied.

Caerulein inhibited the exploratory behaviour in the plus-maze. Time spent in the open part, the number of line crossings and closed arm entries were significantly decreased, whereas the ratio of failed attempts/closed arm entries was increased. The anti-exploratory effect of caerulein was antagonized by the pretreatment with L-365,260 (10 μg/kg), a preferential antagonist at CCKB receptors, but was increased by devazepide (1–100 μg/kg), a preferential CCKA antagonist. L-365,260 (1–100 ⧎/kg) and devazepide (1–100 Fig/kg) given alone did not change the behaviour of rats in the plusmaze test. Caerulein (5 μg/kg) itself did not modify the locomotor activity of rats in open field. However, the concomitant administration of caerulein with devazepide (1–10 μg/kg) reduced the frequency of line crossings and rearings. In the hormonal studies caerulein significantly decreased the cold-induced increase of TSH levels in serum. GH and PRL levels were not markedly affected by caerulein. Pretreatment with devazepide (100 μg/kg) antagonized, while Lr365,260 (100 Ng/kg) even increased, the suppressing effect of caerulein on TSH levels. The concomitant administration of L-365,260 and caerulein reduced the levels of GH, whereas the combination of CCK agonist with devazepide caused the opposite effect. L-365,260 and devazepide alone did not change the levels of hormones in serum.

The results support the idea that CCKA and CCKB receptors exert an opposite influence not only upon the exploratory behaviour in rats (CCKA receptor activation mediates an increase, CCKB receptor activation a decrease) but also upon the secretion of two anterior pituitary hormones, TSH and probably GH (CCKA receptor activation mediates a decrease, CCKB receptor activation an increase).

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References

  • Abelson JL, Neese RM (1990) Cholecystokinin-4 and panic. Arch Gen Psychiatry 47:395

    PubMed  CAS  Google Scholar 

  • Anhut H, Mayer DK, Knepel W (1983) Cholecystokinin-like immunoreactivity of rat medial basal hypothalamus: investigations on a possible hypophysiotropic function. Neuroendocrinology 36:119–124

    Article  PubMed  CAS  Google Scholar 

  • Bradwejn J, de Montigny C (1984) Benzodiazepines antagonize cholecystokinin-induced activation of rat hippocampal neurons. Nature 312:363–364

    Article  PubMed  CAS  Google Scholar 

  • Bradwejn J, Koszycki D, Meterissian G (1990) Cholecystokinin tetrapeptide induces panic attack in patients with panic disorders. Can J Psychiat 35:83–85

    CAS  Google Scholar 

  • Bradwejn J, Koszycki D, Annable L, Du Tertre AC, Reines S, Karkanias C (1992) A dose-ranging study of the behavioral and cardiovascular effect of CCK-tetrapeptide in panic disorder. Biol Psychiatry 32:903–912

    Article  PubMed  CAS  Google Scholar 

  • Branchereau P, Bohme GA, Champagnat J, Moran-Surun MP, Duriex C, Blanchard JC, Roques BP, Denavit-Saubie M (1992) Cholecystokinin-A and cholecystokinin-B receptors in neurons of the brainstem solitary complex of the rat: pharmacological identification. J Pharmacol Exp Ther 260:1433–1440

    PubMed  CAS  Google Scholar 

  • Corp Es, McQuade J, Moran TH, Smith GP (1993) Characterization of type-A and type-B CCK receptor binding sites in rat vagus nerve. Brain Res 623:161–166

    Article  PubMed  CAS  Google Scholar 

  • Crawley JN (1988) Neuronal cholecystokinin. ISI Atlas of Science: Pharmacology 2:84–90. Institute for Scientific Information, Philadelphia, PA, USA

    Google Scholar 

  • Crawley JN (1991) Cholecystokinin-dopamine interactions. Trends Pharmacol Sci 12:232–236

    Article  PubMed  Google Scholar 

  • Crawley JN (1992) Subtype-selective cholecystokinin receptor antagonists block cholecystokinin modulation of dopamine-mediated behaviors in the rat mesolimbic pathway. J Neurosci 12:3380–3391

    PubMed  CAS  Google Scholar 

  • Crawley JN, Hommer DW, Skirboll LR (1985) Topographical analysis of nucleus accumbens sites at which cholecystokinin potentiates dopamine-induced hyperlocomotion in the rat. Brain Res 335:337–341

    Article  PubMed  CAS  Google Scholar 

  • de Montigny C (1989) Cholecystokinin tetrapeptide induces panic like attacks in healthy volunteers. Arch Gen Psychiatry 46:511–517

    PubMed  Google Scholar 

  • Dourish CT, Hawley D, Iversen SD (1988) Enhancement of morphine analgesia and prevention of morphine tolerance in the rat by the cholecystokinin antagonist L364,718. Eur J Pharmacol 147: 469–472

    Article  PubMed  CAS  Google Scholar 

  • Dourish CT, O'Neill MF, Coughlan J, Kitchener SJ, Hawley D, Iversen SD (1990) The selective CCK-B antagonist L365,260 enhances morphine analgesia and prevents morphine tolerance in the rat: evidence for mediation of CCK/opioid interactions by CCK-B receptor. Eur J Pharmacol 176:35–44

    Article  PubMed  CAS  Google Scholar 

  • Fujimoto M, Igano K, Watanabe K, Irie I, Inouye K, Okabayashi T (1985) Effects of caerulein-related peptides on cholecystokinin receptor bindings in brain and pancreas. Biochem Pharmacol 34:1103–1107

    Article  PubMed  CAS  Google Scholar 

  • Gross PM, Wall KM, Wainman DS, Shaver SW (1991) Subregional topography of capillaries of the dorsal vagal complex of rats. II. Physiological properties. J. Comp Neurol 306:83–94

    Article  PubMed  CAS  Google Scholar 

  • Handley SL, Mithani S (1984) Effects of α-adrenergic agonists and antagonists in a maze-exploration model of “fear”-motivated behaviour. Naunyn Schmiedebergs Arch Pharmacol 327:1–5

    Article  PubMed  CAS  Google Scholar 

  • Harro J, Vasar E (1991a) Cholecystokinin-induced anxiety - how is it reflected in studies on exploratory behaviour. Neurosci Biobehav Rev 15:473–477

    Article  PubMed  CAS  Google Scholar 

  • Harro J, Vasar E (1991b) Evidence that CCKB receptors mediate the regulation of exploratory behaviour in the rat. Eur J Pharmacol 193:379–381

    Article  PubMed  CAS  Google Scholar 

  • Harro J, Kiivet R-A, Lang A, Vasar E (1990) Rats with anxious or nonanxious type of exploratory behaviour differ in their brain CCK-8 and benzodiazepine receptor characteristics. Behav Brain Res 39:63–71

    Article  PubMed  CAS  Google Scholar 

  • Harro J, Vasar E, Bradwejn J (1993) CCK in animal and human research on anxiety. Trends Pharmacol Sci 14:244–249

    Article  PubMed  CAS  Google Scholar 

  • Hökfelt T (1991) Neuropeptides in perspective: the last ten years. Neuron 7:867–879

    Article  PubMed  Google Scholar 

  • Kamilaris TC, Johnson EO, Calogero AE, Kalogeras KT, Bernardini KT, Chrousos GP, Gold PW (1992) Cholecystokinin-octapeptide stimulates hypothalamic-pituitary-adrenal function in rats - role of corticotropin-releasing hormone. Endocrinology 130:1764–1774

    Article  PubMed  CAS  Google Scholar 

  • Katsuura G, Ibii N, Matsushita A (1992) Activation of CCK-A receptors induces elevation of plasma corticosterone in rats. Peptides 13:203–205

    Article  PubMed  CAS  Google Scholar 

  • Khosla S, Crawley JN (1988) Potency of L364,718 as an antagonist of the behavioural effects of peripherally administered cholecystokinin. Life Sci 42:153–159

    Article  PubMed  CAS  Google Scholar 

  • Männistö PT (1983) Central regulation of thyrotropin secretion in rats: methodological aspects, problems and some progress. Med Biol 61:92–100

    PubMed  Google Scholar 

  • Männistö PT, Peuranen E, Harro J, Vasar E (1992) Possible role of cholecystokinin-A receptors in the regulation of thyrotropin secretion in male rats. Neuropeptides 23:251–258

    Article  PubMed  Google Scholar 

  • Marshall FH, Barnes S, Hughes J, Woodruff GN, Hunter JC (1991) Cholecystokinin modulates the release of dopamine from the anterior and posterior nucleus accumbens by 2 different mechanisms. J Neurochem 56:917–922

    Article  PubMed  CAS  Google Scholar 

  • McKenzie JM (1958) The bioassay of thyrotropin in serum. Endocrinology 63:372–382

    PubMed  CAS  Google Scholar 

  • Millington WR, Mueller GP, Lavigne GJ (1992) Cholecystokinin type A and type B receptor antagonists produce opposite effects on cholecystokinin-stimulated ß-endorphin secretion from rat pituitary. J Pharmacol Exp Ther 261:454–461

    PubMed  CAS  Google Scholar 

  • Nicoll CS (1967) Bio-assay of prolactin. Analysis of the pigeon crop-sac response to local prolactin injection by an objective and quantitative method. Endocrinology 80:641–655

    Article  PubMed  CAS  Google Scholar 

  • O'Neill MF, Dourish CT, Iversen SD (1991) Hypolocomotion induced by peripheral or central injection of CCK in the mouse is blocked by the CCKA receptor antagonist devazepide but not by the CCKB receptor antagonist L365,260. Eur J Pharmacol 193:203–208

    Article  PubMed  Google Scholar 

  • Palkovits M (1986) Afferents to neuroendocrine cells. In: Ganten D, Pfaff D (eds) Current Topics in Neuroendocrinology, vol. 7. Morphology of hypothalamus and its connections, 1st edn. Springer, Berlin Heidelberg New York

    Google Scholar 

  • Porter JR, Sander LD (1981) The effect of cholecystokinin octapeptide on pituitary-adrenal hormone secretion. Regul Pept 2:245–252

    Article  PubMed  CAS  Google Scholar 

  • Ravard S, Dourish CT (1990) Cholecystokinin and anxiety. Trends Pharmacol Sci 11:271–273

    Article  PubMed  CAS  Google Scholar 

  • Sander LD, Porter JR (1988) Influence of bombesin, CCK, secretin and CRF on corticosterone concentration in the rat. Peptides 9:113 -117

    Article  PubMed  CAS  Google Scholar 

  • Singh L, Field MJ, Hughes J, Menzies R, Oles RJ, Vass CA, Woodruff GN (1991a) The behavioural properties of CI-988, a selective cholecystokinin-B receptor antagonist. Br J Pharmacol 104:239–245

    PubMed  CAS  Google Scholar 

  • Singh L, Lewis AS, Field MJ, Hughes J, Woodruff GN (1991b) Evidence for an involvement of the brain cholecystokinin-B receptor in anxiety. Proc Natl Acad Sci USA 88:1130–1133

    Article  PubMed  CAS  Google Scholar 

  • Soar J, Hewson G, Leighton GE, Hill RG, Hughes J (1989) L364,718 antagonizes the cholecystokinin-induced suppression of locomotor activity. Pharmacol Biochem Behav 33:637–640

    Article  PubMed  CAS  Google Scholar 

  • Studler JM, Reibaud M, Herve D, Blanc G, Glowinski J, Tassin JP (1986) Opposite effects of sulphated cholecystokinin on DA-sensitive adenylate cyclase in two areas of the rat nucleus accumbens. Eur J Pharmacol 126:125–128

    Article  PubMed  CAS  Google Scholar 

  • Tang F, Man WSY (1991) The regional distribution of thyrotropin releasing hormone, leu-enkephalin, met-enkephalin, substance-P, somatostatin and cholecystokinin in the rat brain and pituitary. Neuropeptides 19:287–292

    Article  PubMed  CAS  Google Scholar 

  • Vasar E (1992) Role of cholecystokinin receptors in the regulation of behaviour and in the action of haloperidol and diazepam. Dr Med Sci Thesis, Department of Physiology, University of Tartu, Tartu, Estonia

    Google Scholar 

  • Vasar E, Harro J, Lang A, Pold A, Soosaar A (1991) Differential involvement of CCK-A and CCK-B receptors in the regulation of locomotor activity in the mouse. Psychopharmacology 105: 393–399

    Article  PubMed  CAS  Google Scholar 

  • Vasar E, Soosaar A, Harro J, Lang A (1992) Changes at cholecystokinin receptors induced by long-term treatment with diazepam and haloperidol. Eur Neuropsychopharmacol 2:447–454

    Article  PubMed  CAS  Google Scholar 

  • Vasar E, Lang A, Harro J, Kôks S, Volke V, Sihver S, Bourin M, Bradwejn J, Mannisto PT (1994) Subdiaphragmatic vagotomy does not prevent antiexploratory effect of caerulein in the elevated plusmaze. Neuropeptides 26:39–45

    Article  PubMed  CAS  Google Scholar 

  • Vasar E, Peuranen E, Ööpik T, Harro J, Mannisto PT (1993) Ondansetron, an antagonist of 5-HT3 receptors, antagonizes the antiexploratory effect of caerulein, an agonist of CCK receptors, in the elevated plus-maze. Psychopharmacology 110:213–218

    Article  PubMed  CAS  Google Scholar 

  • Vijayan E, McCann SM (1978) The effects of intraventricular injection of gamma-aminobutyric acid (GABA) on prolactin and gonadotropin release in conscious female rats. Brain Res 155:35–43

    Article  PubMed  CAS  Google Scholar 

  • Wilkinson L (1990) Systat. Intelligent Software (Version 5.0). Systat, Inc., Evanston, IL, USA

    Google Scholar 

  • Woodruff GN, Hill DR, Boden P, Pinnock R, Singh L, Hughes J (1991) Functional role of brain CCK receptors. Neuropeptides 19(1 Suppl): 45–56

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, University of Helsinki, (Siltavuorenpenger 10, Helsinki), P.O. Box 8, FIN-00014, Finland

    P. T. Männistö & E. Peuranen

  2. Institute of Physiology, Tartu University, 18 Ülikooli Street, EST 2400, Tartu, Estonia

    A. Lang & E. Vasar

  3. Psychopharmacology Unit, Tartu University, 18 Ülikooli Street, EST-2400, Tartu, Estonia

    J. Harro

  4. Division of Psychopharmacology, St. Mary's Hospital Centre McGill University, 3830 Avenue Lacombe, H3T 1M5, Montreal, Quebec, Canada

    J. Bradwejn

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  1. P. T. Männistö
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  2. A. Lang
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Correspondence to: P. T. Mannisto at the above address

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Männistö, P.T., Lang, A., Harro, J. et al. Opposite effects mediated by CCKA and CCKB receptors in behavioural and hormonal studies in rats. Naunyn-Schmiedeberg's Arch Pharmacol 349, 478–484 (1994). https://doi.org/10.1007/BF00169136

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  • DOI: https://doi.org/10.1007/BF00169136

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