Abstract
Fifteen minute exposure to a novel environment plus 120 dB sound stimulation produced a three-fold increase in serum corticosterone concentrations in rats. A low dose of intraperitoneally (IP) administered chlordiazepoxide (CDP) (5 mg/kg) attenuated this response, whereas a higher dose (20 mg/kg) elevated corticosterone concentrations in rats not subjected to sound stress. Parallel results were obtained after intracerebroventricular (ICV) drug administration, with a low dose of CDP (5 μg) reducing the sound stress response and higher doses (25 and 50 μg) increasing corticosterone concentrations in unstressed animals. Thus, despite the presence of benzodiazepine (BDZ) receptors at every level of the hypothalamic-pituitary-adrenocortical axis, it appears that BDZs alter the activity of this system via an interaction with BDZ receptors in brain. CL 218,872 (2.5–20 mg/kg), a novel non-BDZ anxiolytic compound, did not attenuate the corticosterone elevation produced by sound stimulation, and also failed to alter baseline corticosterone concentrations in unstressed animals. The fact that CL 218,872 is a selective agonist for brain Type I BDZ receptors suggests that BDZs are not influencing corticosterone secretion through an interaction with this BDZ receptor subtype. Furthermore, these results indicate that stress (as measured by pituitary-adrenocortical activation) can be dissociated from anxiety (as measured by conflict paradigms), thus challenging the validity of the corticosteroid stress test as a screening procedure for anxiolytic activity.
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Benavides J, Malgouris C, Imbault F, Begassat F, Uzan A, Renault C, Dubroeucg MC, Gueremy C, LeFur G (1983) “Peripheral type” benzodiazepine binding sites in rat adrenals: Binding studies with [3]PK 11195 and autoradiographic localization. Arch Int Pharmacodyn Ther 266:38–48
Bizzi A, Ricci MR, Veneroni E, Amato M, Garattini S (1984) Benzodiazepine receptor antagonists reverse the effect of diazepam on plasma corticosterone in stressed rats. J Pharm Pharmacol 36:134–135
Bonnycastle DD, Bradley AJ (1960) Diphenylhydantoin and the release of adrenocorticotropic hormone in the albino rat. Endocrinology 66:355–363
Braestrup C, Schmiechen R, Neef G, Nielsen M, Peterson EN (1982) Interaction of convulsive ligands with benzodiazepine receptors. Science 216:1241–1243
Braestrup C, Squires R (1978) Pharmacological characterization of benzodiazeping receptors in the brain. Eur J Pharmacol 48:263–270
Chabot G, Bressette Y, Gascon AL (1982) Relationship between plasma corticosterone and adrenal epinephrine after diazepam treatment in rats. Can J Physiol Pharmacol 60:589–596
File SE, Pellow S (1985) The effects of putative anxiolytic compounds (PK 8165, PK 9084 and tracazolate) on the rat corticosterone response. Physiol Behav 35:583–586
File SE (1982) The rat corticosterone response: Habituation and modification by chlordiazepoxide. Physiol Behav 29:91–95
File SE, Lister RG, Nutt DJ (1982) Intrinsic actions of benzodiaze-pine antagonists. Neurosci Lett 32:165–168
File SE, Peet LA (1980) The sensitivity of the rat corticosterone response to environmental manipulations and to chronic chlordiazepoxide treatment. Physiol Behav 25:753–758
Gram LF, Christensen P (1986) Benzodiazepine suppression of cortisol secretion: A measure of anxiolytic activity? Pharmacopsychiatry 19:19–22
Grandison L, Guidotti A (1979) Gamma-aminobutyric acid receptor function in rat anterior pituitary: evidence for control of prolactin release. Endocrinology 105:754–759
Hirsch JD, Garrett KM, Beer B (1985) Heterogeneity of benzodiazepine binding sites: A review of recent research. Pharmacol Biochem Behav 23:681–685
Hoogland DR, Miya TS, Bousquent WF (1966) Metabolism and tolerance studies with chlordiazepoxide-2-14C in the rat. Toxicol Appl Pharmacol 9:116–123
Kirk RE (1968) Experimental design: Procedures for the behavioral sciences. Belmont, Brooks/Cole
Krulik R, Crny M (1971) Effect of chlordiazepoxide on stress in rats. Life Sci 10:145–151
Lahti RA, Barsuhn C (1974) The effect of minor tranquilizers on stress-induced increases in rat plasma corticosteroids. Psychopharmacologia 35:215–220
Lahti RA, Barsuhn C (1975) The effect of various doses of minor tranquilizers on plasma corticosteroids in stressed rats. Res Commun Chem Pathol Pharmacol 11:595–603
LeFur G, Guilloux F, Mitrani N, Mizoule J, Uzan A (1979) Relationships between plasma corticosteroids and benzodiazepines in stress. J Pharmacol Exp Ther 211:305–308
LeFur G, Mizoule J, Burgevin MC, Ferris O, Heaulme M, Gauthier A, Gueremy C, Uzan A (1981) Multiple benzodiazepine receptors: evidence of a dissociation between anticonflict and anticonvulsant properties by PK 8165 and PK 9084. Life Sci 28:1439–1448
Lippa AS, Critchett D, Sano MC, Klepner CA, Greenblatt EN, Coupet J, Beer B (1979) Benzodiazepine receptors: cellular and behavioral characteristics. Pharmacol Biochem Behav 10:831–843
Marangos PJ, Patel J, Boulenger JP, Clark-Rosenberg R (1982) Characterization of peripheral-type benzodiazepine binding sites in brain using [3H] Ro 5–4864. Mol Pharmacol 22:26–32
Marc V, Morselli PL (1969) Effect of diazepam on plasma corticosterone levels in the rat. J Pharm Pharmacol 21:784–786
McElroy JF, Feldman RS (1982) Generalization between benzodiazepine-and triazolopyridazine-elicited discriminative cues. Pharmacol Biochem Behav 17:709–713
McElroy JF, Feldman RS, Meyer JS (1986) A comparison between chlordiazepoxide and CL 218,872, a synthetic nonbenzodiazepine ligand for benzodiazepine receptors, on serotonin and catecholamine turnover in brain. Psychopharmacology 88:105–108
McElroy JF, Flemming RL, Feldman RS (1985) A comparison between chlordiazepoxide and CL 218,872 — a synthetic nonbenzodiazepine ligand for benzodiazepine receptors — on spontaneous locomoter activity in rats. Psychopharmacology 85:224–226
McElroy JF, Miller JM, Meyer JS (1984) Fenfluramine, p-chloroamphetamine and p-fluoroamphetamine stimulation of pituitary-adrenocortical activity in rat: evidence for differences in site and mechanism of action. J Pharmacol Exp Ther 228:593–599
Meyer JS (1983) Early adrenalectomy stimulates subsequent growth and development of the rat brain. Exp Neurol 28:432–446
Mohler H, Okada T (1977) Benzodiazepine receptor: Demonstration in the central nervous system. Science 198:849–851
Mormede P, Dantzer R, Perio A (1984) Relationship of the effects of the benzodiazepine derivative clorazepate on corticosterone secretion with its behavioural actions. Antagonism by Ro 15–1788. Pharmacol Biochem Behav 21:839–843
Nielsen M, Braestrup C (1980) Ethyl β-carboline-3-carboxylate shows differential benzodiazepine receptor interaction. Nature 286:606–607
Norton PRE (1971) Some endocrine aspects of barbiturate dependence. Br J Pharmacol 41:317–330
Oakley NR, Jones BJ, Straughan DW (1984) The benzodiazepine receptor ligand CL 218,872 has both anxiolytic and sedative properties in rodents. Neuropharmacology 23:797–802
Rerup C, Hedner P (1962) The effect of pentobarbital (Nembutal, Mebumal NFN) on corticotrophin release in the rat. Acta Endocrinol 39:518–526
Schoemaker H, Boles R, Horst WD, Yamamura H (1983) Specific high-affinity binding sites for [3H] Ro 5–4864 in rat brain and kidney. J Pharmacol Exp Ther 225:61–69
Sellers EM, Busto V (1982) Benzodiazepines and ethanol: assessment of the effects and consequences of psychotropic drug interactions. J Clin Pharmacol 2:249–262
Sieghart W (1985) Binding of various benzodiazepine receptor ligands to different benzodiazepine receptor subtypes. Pharmacopsychiatry 18:160–162
Squires RF, Benson DI, Braestrup C, Coupet J, Klepner CA, Myers V, Beer B (1979) Some properties of brain specific benzodiazepine receptors: new evidence for multiple receptors. Pharmacol Biochem Behav 10:825–830
Squires R, Braestrup C (1977) Benzodiazepine receptors in brain. Nature 266:732–734
Torrellas A, Guazo C, Borrell J (1980) Effects of acute and prolonged administration of chlordiazepoxide upon the pituitary adrenal activity and brain catecholamines in sound stressed and unstressed rats. Neuroscience 5:2289–2295
Treit D (1985) Animal models for the study of anti-anxiety agents: A review. Neurosci Biobehav Rev 9:203–222
Vogel JR, Beer D, Clody DE (1971) A simple and reliable conflict procedure for testing anti-anxiety agents. Psychopharmacologia 21:1–7
Wickstrom E, Giercksky KE (1980) Comparative study of zopiclone, a novel hypnotic, and three benzodiazepines. Eur J Clin Pharmacol 17:93–99
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McElroy, J.F., Miller, J.M. & Meyer, J.S. Comparison of the effects of chlordiazepoxide and CL 218,872 on serum corticosterone concentrations in rats. Psychopharmacology 91, 467–472 (1987). https://doi.org/10.1007/BF00216012
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DOI: https://doi.org/10.1007/BF00216012