Abstract
Previous studies have used the elevated plus maze to test for “anxiolytic” drugs in rats. The present study demonstrates that guinea-pigs handled daily from birth exhibit similar behaviour to rats on the plus maze. Pretreatment with diazepam (1.0 mg/kg) significantly increased the time the animals spent in the open arms and amount of entries into the open arms. Using intra-cortical microdialysis on exposure of the guinea-pig to the elevated plus maze resulted in increased extracellular 5-HT in the frontal cortex. Diazepam reduced, but not significantly, the increase in extracellular 5-HT and produced an “anxiolytic” profile of behaviour. Pretreatment with the benzodiazepine antagonist flumazenil (10.0 mg/kg) fully antagonised the behavioural effects of diazepam. Flumazenil also reduced the effect of diazepam on the increase in extracellular 5-HT observed on exposure of the guinea-pig to the elevated plus maze. Flumazenil alone decreased basal extracellular cortical 5-HT but had no effect on behaviour in the elevated plus maze. The results show that an increase in extracellular 5-HT occurs in the guinea-pig exposed to aversive conditions. While it remains to be determined whether the “anxiolytic” effects of diazepam in the guinea-pig are causally associated with decreased extracellular 5-HT, it is of interest that the selective benzodiazepine antagonist also prevented the increase in basal extracellular 5-HT produced by the exposure to the elevated plus maze but had no effect on behaviour. Results indicate that there is no simple relationship between inhibition of 5-HT release and the “anxiolytic” action of benzodiazepines.
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References
Azmitia EC, Segal M (1978) An autoradiographic analysis of the differential ascending projections of the dorsal and median raphe nuclei in the rat. J Comp Neurol 179:641–668
Bayard J (1957) The duration of tonic immobility in guinea pigs J Comp Physiol Psychol 50:130–133
Balfour DJK (1980) Effects of GABA and diazepam on [3H] - serotonin release from hippocampal synaptosomes. Eur J Pharmacol 68:11–16
Birmelin I (1990) Behaviour of pet animals. DTW Dtsch Tierarztl Wochenschr 97:243–247
Boix F, Teruel AF, Escorihuela RM, Tobena A (1990) Handling-habituation prevents the effects of diazepam and alpralozam on brain serotonin levels in rats. Behav Brain Res 36:209–215
Brett RR, Pratt JA (1990) Chronic handling modifies the anxiolytic effect of diazepam in the elevated plus-maze. Eur J Pharmacol 178:135–138
Carboni E Di Chiara G (1989) Serotonin release estimated by transcortical dialysis in freely moving rats. Neuroscience 32:637–646
Collinge J, Pycock CJ (1982) Differential actions of diazepam on the release of [3H] 5-hydroxytryptamine from cortical and midbrain raphe slices in the rat. Eur J Pharmacol 85:9–14
Dantzer R, Perio A (1982) Behavioural evidence for partial agonist properties of Ro 15–1788, a benzodiazepine receptor antagonist. Eur J Pharmacol 81:655–658
Deakin JFW, Graeff FG (1991) 5-HT and mechanisms of defence J Psychopharmacol 5:305–315
Dominic JA, Sinha AK, Barchas JD (1975) Effect of benzodiazepine compounds on brain amine metabolism Eur J Pharmacol 32:124–127
Falk JL, Tang M (1984) Midalozam-induced increase in NaCl solution ingestion: differential effect of the benzodiazepine antagonists Ro 15–1788 and CGS 8216. Pharmacol Biochem Behav 21:965–968
File SE, Pellow S (1984) The anxiogenic action of Ro 15–1788 is reversed by chronic, but not by acute, treatment with chlordiazepoxide. Brain Res 310:154–156
File SE, Pellow S (1985) The benzodiazepine receptor antagonist Ro 15–1788 has anxiogenic activity in four animal tests of anxiety. Br J Pharmacol 84:103P
File SE, Lister RG, Nutt DJ (1982a) The anxiogenic action of benzodiazepine antagonists. Neuropharmacology 21:1033–1037
File SE, Lister RG, Nutt DJ (1982b) Intrinsic actions of benzodiazepine antagonists. Neurosci Lett 32:165–168
Gallager DW (1978) Benzodiazepine: potentation of a GABA inhibitory response in dorsal raphe nucleus. Eur J Pharmacol 49:133–143
Graeff FG, Schoenfeld RI (1970) Tryptamine mechanism in punished and nonpunished behaviour J Pharmacol Exp Ther 173:277–283
Handley SL, Mithani S (1984) Effects of alpha-adrenoceptor agonists and antagonists in a maze-exploration model of “fear”-motivated behaviour. Naunyn-Schmiedeberg Arch Pharmacol 327:1–5
Hitchcott PK, File SE, Ekwuru M, Neal MJ (1990) Chronic diazepam treatment in rats causes long-lasting changes in central [3H]-5-hydroxytryptamine and [14C]-g-aminobutyric acid release. Br J Pharmacol 99:11–12
Hoyer D, Middlemiss DN (1989) Species differences in the pharmacology of terminal 5-HT autoreceptors in mammalian brain. TIPS 10:130–132
Lawrence AJ, Marsden CA (1990) The effect of systemic 5-carboxamidotryptamine on extracellular levels of 5-HT in the freely moving guinea-pig. Br J Pharmacol 101:519P
Lawrence AJ, Marsden CA (1992) Terminal autoreceptor control of 5-hydroxytryptamine as measured by in vivo microdialysis in the conscious guinea-pig. J Neurochem 58:142–146
Lista A, Arbilla S, Langer SZ (1988) Modulation of electrically evoked release of 5-[3H] hydroxytryptamine from rat cerebral cortex: effect of alpidem, CL 218872 and diazepam. J Neurochem 51:1414–1421
Lista A, Blier P, De Montigny C (1990) Benzodiazepine receptors modulate 5-hydroxytryptamine neurotransmission in the rat hippocampus: in vivo electrophysiological evidence. J Pharmacol Exp Ther 254:318–323
Lister RG (1987) The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology 92:180–185
Lister RG, File SE (1983) Changes in regional concentrations in the rat brain of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid during the development of tolerance to the sedative action of chlordiazepoxide. J Pharm Pharmacol 35:601–603
Luscombe GP, Mazurkiewicz SE, Buckett WR (1991) Flumazenil antagonises the anxiolytic effect of chloridazepoxide, buspirone and dothiepin in the elevated plus-maze. Br J Pharmacol 104:216P
Marsden CA (1985) In vivo monitoring of pharmacological and physiological changes in endogenous serotonin release and metabolism. In: Green AR (ed) Neuropharmacology of serotonin. Oxford University Press, Oxford, pp 3–27
Marsden CA, Martin KF, Routlege C, Brazell MP, Maidment NT (1986) Application of intracerebral dialysis and in vivo voltametry to pharmacological and physiological studies of amine neurotransmitters. Ann NY Acad Sci 473:106–125
Massotti M, Schlichting JL, Antonacci MD, Giusti P, Memo M, Costa E, Guidotti A (1991) gamma-Aminobutyric acid A receptor heterogeneity in rat central nervous system: studies with clonazepam and other benzodiazepine ligands. J Pharmacol Exp Ther 256:1154–1160
Montgomery KC (1955) The relation between fear induced by novel stimulation and exploratory behaviour. J Comp Physiol Psychol 48:254–260
Olsen RW (1981) GABA-benzodiazepine-barbiturate receptor interactions. J Neurochem 37:1–13
Pei Q, Zetterstroem T, Fillenz M (1989) Both systemic and local administration of benzodiazepine agonist inhibit the in vivo release of 5-HT from the ventral hippocampus Neuropharmacology 28 [10]:1061–1066
Pellow S, File SE (1986) Anxiolytic and anxiogenic drug effects on exploratory activity in an elevated plus-maze: a novel test of anxiety in the rat. Pharmacol Biochem Behav 24:525–529
Pellow S, Chopin P, File SE, Briley M (1985) Validation of open: closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14:149–167
Racke K, Schworer H, Kilbinger H (1990) Effects of the benzodiazepine receptor agonist midazolam and antagonist flumazenil on 5-hydroxytryptamine release from guinea-pig intestine in vitro. Indirect support for a “natural” benzodiazepine-like substance in the intestine. Naunyn-Schmiedeberg's Arch Pharmacol 341:1–7
Raeder TA (1981) Distribution of catecholamines and serotonin in the rat cerebral cortex: absolute levels and relative proportions. J Neural Transm 50:13–27
Robertson HA, Riives ML (1983) A benzodiazepine antagonist is an anticonvulsant in an animal model for limbic epilepsy. Brain Res 270:380–382
Rössner W (1965) Stereotaktischer Hirnatlas vom Meerschweinchen. Pallas, Lochham
Saner A, Pletscher A (1979) Effect of diazepam on cerebral 5-hydroxytryptamine synthesis. Eur J Pharmacol 55:315–318
Smart JL, Adlard BPF (1974) A water-maze test of learning ability for guinea-pigs. Lab Anim 8:311–315
Soubrié P, Blas C, Ferron A, Glowinski J (1983) Chlordiazepoxide reduces in vivo serotonin release in the basal ganglia ofencephacele isole but not anaesthetized cats: evidence for a dorsal raphe site of action. J Pharmacol Exp Ther 226:526–532
Stein L, Wise D, Berger BD (1973) Anti-anxiety action of benzodiazepines: decrease in activity of serotonin neurons in the punishment system. In: Garattini S, Massini E, Randall LO (eds) The benzodiazepines Raven Press, New York, pp 299–326
Trulson ME, Preussler DW, Howell GA, Frederickson CJ (1982) Raphe unit activity in freely moving cats: effects of benzodiazepines. Neuropharmacology 21:1045–1050
Ungerstedt U, Herrera-Marschitz M, Jungnelius U, Stahle L, Tossman U, Zetterstrom T (1982) Dopamin synaptic mechanisms reflected in studies combining behavioural recordings and brain dialysis. Adv Biosci 37:219–231
Waeber C, Schoeffter P, Palacios JM, Hoyer D (1989) 5-HT1D receptors in guinea pig and pidgeon brain. Radioligand binding and biochemical studies. Naunyn-Schmiedeberg's Arch Pharmacol 340:486–494
Wise CD, Berger BD, Stein L (1972) Benzodiazepines: anxiety-reducing reducing activity by reduction of serotonin turnover in the rat brain. Science 177:180–183
Wright IK (1991) 5-HT function in rodent models of anxiety. Ph D Thesis, Nottingham University, pp 76–86
Wright IK, Upton N, Marsden CA (1992) Effect of established and putative anxiolytics on extracellular 5-HT and 5-HIAA in the ventral hippocampus of rats during behaviour on the elevated X-maze. Psychopharmacology 109:338–346
Zilles K, Wree A, Dausch ND (1990) Anatomy of the neocortex: neurochemical organization. In: Kolb B, Tees RC (eds) The cerebral cortex of the rat. MIT Press, Cambridge, Massachusetts, pp 113–150
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Rex, A., Marsden, C.A. & Fink, H. Effect of diazepam on cortical 5-HT release and behaviour in the guinea-pig on exposure to the elevated plus maze. Psychopharmacology 110, 490–496 (1993). https://doi.org/10.1007/BF02244657
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DOI: https://doi.org/10.1007/BF02244657