Summary
The activity of SR 27897, a potent and selective CCK-A vs CCK-B receptor antagonist (Ki = 0.2 nM on guinea-pig pancreas vs 2000 nM on rat brain) was studied on behavioural, electrophysiological and biochemical effects induced by peripheral or central injection of CCK-8S. For comparative purposes, devazepide, a reference CCK-A receptor antagonist, was investigated in these same models. CCK-induced hypophagia and CCK-induced hypolocomotion in rats, two behavioural changes associated with the stimulation of peripheral CCK-A receptors, were dose-dependently antagonized by SR 27897 (ED50 = 0.003 and 0.002 mg/kg i.p., respectively) and devazepide (ED50 = 0.02 and 0.1 mg/kg i.p., respectively). CCK-induced decrease of cerebellar cGMP levels in mice was also reduced by SR 27897 (ED50 = 0.013 mg/kg) and by devazepide (0.084 mg/kg). The CCK-induced turning behaviour after intrastriatal injection in mice, and the potentiation of the rate suppressant activity of apomorphine on rat DA neurons, were blocked by higher doses of SR 27897 and devazepide, consistent with the probable central origin of these effects. The respective ED50s were 0.2 mg/kg i.p. for SR 27897 and 4.9 mg/kg i.p. for devazepide in the former model, while the respective minimal effective doses were 1.25 and 5 mg/kg i.p. in the latter test. In most tests the i.p./p.o. ratio for SR 27897 was near unity, suggesting a high oral bioavailability of the compound. Taken together, these findings support the notion that SR 27897 behaves as a potent CCK-A antagonist able to cross the blood brain barrier.
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References
Chiodo LA (1988) Dopamine-containing neurons in the mammalian central nervous system: electrophysiology and pharmacology. Neurosci Biobehav Rev 12:49–91
Chiodo LA, Freeman AS, Bunney BS (1987) Electrophysiological studies on the specificity of the cholecystokinin antagonist proglumide. Brain Res 410:205–211
Crawley JN, Hays SE, Paul SM (1981) Vagotomy abolishes the inhibitory effects of cholecystokinin on rat exploratory behaviors. Eur J Pharmacol 73:379–380
Dourish CT, Ruckert AC, Tattersall FD, Iversen SD (1989a) Evidence that decreased feeding induced by systemic injection of cholecystokinin is mediated by CCK-A receptors. Eur J Pharmacol 173:233–234
Dourish CT, Rycroft W, Iversen SD (1989b) Postponement of satiety by blockade of brain cholecystokinin (CCK-B) receptors. Science 245:1509–1511
Freeman AS, Chiodo LA (1988) Electrophysiological effects of cholecystokinin octapeptide on identified rat nigrostriatal dopaminergic neurons. Brain Res 439:266–274
Gully D, Fréhel D, Marcy C, Spinazzé A, Lespy L, Néliat G, Maffrand JP, Le Fur G (1993) Peripheral biological activities of SR 27897: a new potent non-peptide antagonist of CCK A receptors. Eur J Pharmacol 232:13–19
Hewson G, Leighton GE, Hill RG, Hughes J (1988) The cholecystokinin receptor antagonist L364,718 increased food intake in the rat by attenuation of the action of endogenous cholecystokinin. Br J Pharmacol 93:79–84
Hill DR, Woodruff GN (1990) Differentiation of central cholecystokinin receptor binding sites using the non-peptide antagonists MK-329 and L365,260. Brain Res 526:276–283
Hill DR, Campbell NJ, Shaw TM, Woodruff GN (1987) Autoradiographic localization and biochemical characterization of peripheral type CCK receptors in rat CNS using highly selective nonpeptide CCK antagonists. J Neurosci 7:2967–2976
Hirosue Y, Inui A, Miura M, Nakajima M, Okita M, Himori N, Baba S, Kasuga M (1992) Effects of CCK antagonists on CCK-induced suppression of locomotor activity in mice. Peptides 13:155–157
Hökfelt T, Skirboll L, Rehfeld JH, Goldstein M, Markey K, Dann O (1980) A subpopulation of mesencephalic dopamine neurons projecting to limbic areas contains a cholecystokinin-like peptide: evidence from immunohistochemistry combined with retrograde tracing. Neuroscience 5:2092–2124
Hommer DW, Stener G, Crawley NJ, Paul SM, Skirboll LR (1986) Cholecystokinin dopamine coexistence: electrophysiological actions corresponding to cholecystokinin receptor subtype. J Neurosci 6:3039–3043
Innis RB, Snyder SH (1980) Distinct cholecystokinin receptors in brain and pancreas. Proc Natl Acad Sci USA 77:6917–6921
Kelland MD, Zhang J, Chiodo LA, Freeman AS (1991) Receptor selectivity of cholecystokinin effects on mesoaccumbens dopamine neurons. Synapse 8:137–143
Laferrere B, Nguygen M, Bonhomme G, Legall A, Basdevant A, Guy-Grand B (1991) Effect of BIM-18216, a novel cholecystokinin receptor antagonist, on food intake reduction induced by cholecystokinin. Behav Neurosci 105:707–711
Lowry O, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275
Minabe Y, Ashby CR, Wang RY (1991) The CCK-A receptor antagonist devazepide but not the CCK-B receptor antagonist L365,260 reverses the effects of chronic clozapine and haloperidol on midbrain dopamine neurons. Brain Res 549:151–154
Moran TH, Ameglio PJ, Schwartz GJ, McHugh PR (1992) Blockade of type A, not type B, CCK receptors attenuates satiety actions of exogenous and endogenous CCK. Am J Physiol 262 (Regulatory Integrative Comp Physiol 31):R46-R50
Murphy RB, Smith GP, Schneider LH, Gibbs J (1992) Peripheral factors in the mediation of cholecystokinin-induced satiety as assessed by comparative potencies of cholecystokinin antagonists. Peptides 13:77–81
Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic Press, Sydney
Silver AJ, Flood JF, Song AM, Morley JE (1989) Evidence for a physiological role of CCK in the regulation of food intake in mice. Am J Physiol 256 (Regulatory Integrative Comp Physiol 25):R646-R652
Singh L, Lewis AS, Field MJ, Hughes J, Woodruff GN (1991) Evidence for an involvement of the brain cholecystokinin B receptor in anxiety. Neurobiology 88:1133–1330
Smith GP, Jerome C, Cushin BJ, Eterno R, Simansky KJ (1981) Abdominal vagotomy blocks the satiety effect of cholecystokinin in the rat. Science 213:1036–1037
Soar J, Hewson G, Leighton GE, Hill RG, Hughes J (1989) L-364,718, antagonizes the cholecystokinin-induced suppression of locomotor activity. Pharmacol Biochem Behav 33:637–640
Steiner AL, Parker CW, Kipnis DM (1972) Radioimmunoassay for cyclic nucleotides. I. Preparation of antibodies and coiodinated cyclic nucleotides. J Biol Chem 247:1106–1115
Tanganelli S, Fuxe K, Von Euler G, Agnati LF, Ferraro L, Ungerstedt U (1990) Involvement of cholecystokinin receptors in the control of striatal dopamine autoreceptors. Naunyn-Schmiedeberg's Arch Pharmacol 342:300–304
Wieterlak EP, Maier SF, Watkins LR (1992) Cholecystokinin antianalgesia: safety cues abolish morphine analgesia. Science 256:830–833
Williams JA (1982) Cholecystokinin: a hormone and a neurotransmitter. Biomed Res 3:107–121
Wood PL, Steel DJ, Kim HS, Petrack B, Altar A (1988) Inhibition of climbing and mossy fiber input to mouse cerebellar Purkinje cells by cholecystokinin. J Pharmac Exp Ther 244:58–62
Woodruff GN, Hill DR, Boden P, Pinnock R, Singh L, Hugues J (1991) Functional role of brain CCK receptors. Neuropeptides 19 [Suppl]:45–56
Worms P, Gueudet C, Biziere K (1986a) Induction of turning by direct intrastriatal injection of dopaminomimetic drugs in mice: pharmacological analysis of a simple screening model. Life Sci 39:2199–2208
Worms P, Martinez J, Briet C, Castro B, Bizière K (1986b) Evidence for dopaminomimetic effect of intrastriatally injected cholecystokinin octapeptide in mice. J Pharmacol 121:395–401
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Poncelet, M., Arnone, M., Heaulme, M. et al. Neurobehavioural effects of SR 27897, a selective cholecystokinin type A (CCK-A) receptor antagonist. Naunyn-Schmiedeberg's Arch Pharmacol 348, 102–107 (1993). https://doi.org/10.1007/BF00168544
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DOI: https://doi.org/10.1007/BF00168544