Abstract
Rationale
GABAA receptors containing an α2 subunit are proposed to mediate the anxiolytic effect of benzodiazepines (BZ) based on studies in transgenic mice using unconditioned models of anxiety. Conditioned models of anxiety were not assessed and are rarely encountered in phenotyping of genetically modified animals. The novel benzodiazepine site ligand L838,417 is a partial agonist at GABAA receptors containing an α2, α3 or α5 subunit and an antagonist at α1 receptors, giving an anxiolytic profile devoid of sedation. However, this compound has not previously been assessed in mice.
Objectives
(1) Establish the Vogel conflict test (VCT) in C57BL/6J mice and validate it with a range of pharmacological tools and (2) compare the full and partial GABAA receptor positive modulators chlordiazepoxide (CDP) and bretazenil (BRZ), respectively, with the subtype selective ligands zolpidem (ZOL; α1 selective) and L838,417.
Results
(1) enhanced thirst (water deprivation or isoproterenol administration), analgesia (lamotrigine) or cognitive impairment (MK-801) did not generate false positives in the VCT; (2) CDP and BRZ engendered linear dose-related anti-conflict effects and also increased unpunished drinking; (3) L838,417 engendered a bell-shaped anti-conflict effect and did not increase unpunished drinking; (4) the anti-conflict effect of CDP and L838,417 were antagonised by flumazenil, whereas BRZ's effect was insensitive to this antagonist; and (5) ZOL induced motoric deficits and no anti-conflict effect.
Conclusion
We have established the VCT in C57BL/6J mice and validated this test behaviourally, physiologically and pharmacologically. The novel GABAA receptor ligand L838,417 was anxiolytic in this mouse model, and unlike the non-selective compounds, had no effect on unpunished drinking.
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Abbreviations
- 5-HT:
-
5-hydroxytryptamine
- 8-OH-DPAT:
-
8-hydroxy-2-(di-n-propylamino)tetralin
- ANOVA:
-
Analysis of variance
- BRZ:
-
bretazenil
- BZ:
-
benzodiazepine
- CDP:
-
chlordiazepoxide
- FLU:
-
flumazenil
- GABA:
-
gamma-aminobutyric acid
- i.p.:
-
intraperitoneal
- ISO:
-
isoproterenol
- mA:
-
milliampere
- NS:
-
not significant
- NMDA:
-
Nmethyl-d-asparic acid
- Veh:
-
vehicle
- VCT:
-
Vogel conflict test
- ZOL:
-
zolpidem
References
Agmo A, Pruneda R, Guzman M, Gutierrez M (1991) GABAergic drugs and conflict behavior in the rat: lack of similarities with the actions of benzodiazepines. Naunyn-Schmiedeberg's Arch Pharmacol 344:314–322
Anagnostopoulos AV, Mobraaten LE, Sharp JJ, Davisson MT (2001) Transgenic and knockout databases: behavioral profiles of mouse mutants. Physiol Behav 73:675–689
Benke D, Michel C, Mohler H (1997) GABA(A) receptors containing the alpha4-subunit: prevalence, distribution, pharmacology, and subunit architecture in situ. J Neurochem 69:806–814
Blackburn-Munro G, Ericksen HK (2004) Antiepileptics in the treatment of neuropathic pain: evidence from animal models. Curr Pharm Des (in press)
Boissier JR, Simon P, Aron C (1968) A new method for rapid screening of minor tranquillizers in mice. Eur J Pharmacol 4:145–151
Borsini F, Podhorna J, Marazziti D (2002) Do animal models of anxiety predict anxiolytic-like effects of antidepressants? Psychopharmacology (Berl) 163:121–141
Brauer HR, Nowicki PW, Catalano G, Catalano MC (2002) Panic attacks associated with citalopram. South Med J 95:1088–1089
Brocco MJ, Koek W, Degryse AD, Colpaert FC (1990) Comparative studies on the anti-punishment effects of chlordiazepoxide, buspirone and ritanserin in the pigeon, Geller–Seifter and Vogel conflict procedures. Behav Pharmacol 1:403–418
Burghardt NS, Sullivan GM, McEwen BS, Gorman JM, LeDoux JE (2004) The selective serotonin reuptake inhibitor citalopram increases fear after acute treatment but reduces fear with chronic treatment: a comparison with tianeptine. Biol Psychiatry 55:1171–1178
Carli M, Samanin R (1982) Evidence that agents increasing water consumption do not necessarily generate “false positives” in conflict procedures using water as a reinforcer. Pharmacol Biochem Behav 17:1–3
Conti LH, Maciver CR, Ferkany JW, Abreu ME (1990) Footshock-induced freezing behavior in rats as a model for assessing anxiolytics. Psychopharmacology (Berl) 102:492–497
Cooper SJ (1982) Benzodiazepine mechanisms and drinking in the water-deprived rat. Neuropharmacology 21:775–780
Cooper SJ (1991) Ingestional responses following benzodiazepine receptor ligands, selective 5-HT1A agonists and selective 5-HT3 receptor antagonists. In: Rodgers RJ, Cooper SJ (eds) 5-HT1A agonists, 5-HT3 antagonists and benzodiazepines. Their comparative pharmacology. Wiley, Chichester, pp 233–265
Crawley JN, Belknap JK, Collins A, Crabbe JC, Frankel W, Henderson N, Hitzemann RJ, Maxson SC, Miner LL, Silva AJ, Wehner JM, Wynshaw-Boris A, Paylor R (1997) Behavioral phenotypes of inbred mouse strains: implications and recommendations for molecular studies. Psychopharmacology (Berl) 132:107–124
Crestani F, Martin JR, Mohler H, Rudolph U (2000) Mechanism of action of the hypnotic zolpidem in vivo. Br J Pharmacol 131:1251–1254
Crestani F, Mohler H, Rudolph U (2001) Anxiolytic action of diazepam: mediated by GABAA receptors containing the α2 subunit. Trends Pharmacol Sci 22:403
Czech DA, Vander Zanden JM (1991) Drinking behavior in the spiny mouse (Acomys cahirinus) following putative dipsogenic challenges. Pharmacol Biochem Behav 38:913–916
Dalvi A, Rodgers RJ (1999) Behavioral effects of diazepam in the murine plus-maze: flumazenil antagonism of enhanced head dipping but not the disinhibition of open-arm avoidance. Pharmacol Biochem Behav 62:727–734
Davis M (1979) Diazepam and flurazepam: effects on conditioned fear as measured with the potentiated startle paradigm. Psychopharmacology (Berl) 62:1–7
Dekeyne A, Brocco M, Adhumeau A, Gobert A, Millan MJ (2000) The selective serotonin (5-HT)1A receptor ligand, S15535, displays anxiolytic-like effects in the social interaction and Vogel models and suppresses dialysate levels of 5-HT in the dorsal hippocampus of freely-moving rats. A comparison with other anxiolytic agents. Psychopharmacology (Berl) 152:55–66
Depoortere H, Zivkovic B, Lloyd KG, Sanger DJ, Perrault G, Langer SZ, Bartholini G (1986) Zolpidem, a novel nonbenzodiazepine hypnotic. I. Neuropharmacological and behavioral effects. J Pharmacol Exp Ther 237:649–658
De Vry J, Benz U, Schreiber R, Traber J (1993) Shock-induced ultrasonic vocalization in young adult rats: a model for testing putative anti-anxiety drugs. Eur J Pharmacol 249:331–339
Di Scala G, Oberling P, Rocha B, Sandner G (1992) Conditioned place preference induced by Ro 16-6028, a benzodiazepine receptor partial agonist. Pharmacol Biochem Behav 41:859–862
File SE, Kenny PJ, Ouagazzal AM (1998) Bimodal modulation by nicotine of anxiety in the social interaction test: role of the dorsal hippocampus. Behav Neurosci 112:1423–1429
Flores P, Pellon R (2000) Antipunishment effects of diazepam on two levels of suppression of schedule-induced drinking in rats. Pharmacol Biochem Behav 67:207–214
Gonzalez LE, File SE (1997) A five minute experience in the elevated plus-maze alters the state of the benzodiazepine receptor in the dorsal raphe nucleus. J Neurosci 17:1505–1511
Griebel G, Perrault G, Tan S, Schoemaker H, Sanger DJ (1999) Comparison of the pharmacological properties of classical and novel BZ-omega receptor ligands. Behav Pharmacol 10:483–495
Griebel G, Belzung C, Perrault G, Sanger DJ (2000) Differences in anxiety-related behaviours and in sensitivity to diazepam in inbred and outbred strains of mice. Psychopharmacology (Berl) 148:164–170
Griebel G, Simiand J, Serradeil-Le Gal C, Wagnon J, Pascal M, Scatton B, Maffrand JP, Soubrie P (2002) Anxiolytic- and antidepressant-like effects of the non-peptide vasopressin V1b receptor antagonist, SSR149415, suggest an innovative approach for the treatment of stress-related disorders. Proc Natl Acad Sci U S A 99:6370–6375
Itoh J, Nabeshima T, Kameyama T (1991) Utility of an elevated plus-maze for dissociation of amnesic and behavioral effects of drugs in mice. Eur J Pharmacol 194:71–76
Kennett GA, Trail B, Bright F (1998) Anxiolytic-like actions of BW 723C86 in the rat Vogel conflict test are 5-HT2B receptor mediated. Neuropharmacology 37:1603–1610
Korsgaard MGP, Hartz BP, Brown WD, Ahring PK, Strøbæk D, Mirza NR (2005) Kv7 channel modulators: novel anxiolytics. J Pharmacol Exp Ther 314:282–292
Kuribara H, Haraguchi H, Tadokoro S (1989) Anticonflict effect of caffeine: investigation by punishment and hypertonic NaCl solution procedures in mice. Arukoru Kenkyu to Yakubutsu Izon 24:144–153
Kuribara H, Fujiwara S, Yasuda H, Tadokoro S (1990) The anticonflict effect of MK-801, an NMDA antagonist: investigation by punishment procedure in mice. Jpn J Pharmacol 54:250–252
Liao JF, Hung WY, Chen CF (2003) Anxiolytic-like effects of baicalein and baicalin in the Vogel conflict test in mice. Eur J Pharmacol 464:141–146
Loiseau F, Le Bihan C, Hamon M, Thiebot MH (2003) Distinct effects of diazepam and NK1 receptor antagonists in two conflict procedures in rats. Behav Pharmacol 14:447–455
Low K, Crestani F, Keist R, Benke D, Brunig I, Benson JA, Fritschy JM, Rulicke T, Bluethmann H, Mohler H, Rudolph U (2000) Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290:131–134
Maickel RP, Maloney GJ (1973) Effects of various depressant drugs on deprivation-induced water consumption. Neuropharmacology 12:777–782
Maruyama Y, Kuribara H, Kishi E, Weintraub ST, Ito Y (2001) Confirmation of the anxiolytic-like effect of dihydrohonokiol following behavioural and biochemical assessments. J Pharm Pharmacol 53:721–725
McKernan RM, Rosahl TW, Reynolds DS, Sur C, Wafford KA, Atack JR, Farrar S, Myers J, Cook G, Ferris P, Garrett L, Bristow L, Marshall G, Macaulay A, Brown N, Howell O, Moore KW, Carling RW, Street LJ, Castro JL, Ragan CI, Dawson GR, Whiting PJ (2000) Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype. Nat Neurosci 3:587–592
Millan MJ, Brocco M (2003) The Vogel conflict test: procedural aspects, gamma-aminobutyric acid, glutamate and monoamines. Eur J Pharmacol 463:67–96
Mirza NR, Bright JL, Stanhope KJ, Wyatt A, Harrington NR (2005) Lamotrigine has an anxiolytic-like profile in the rat conditioned emotional response test of anxiety: a potential role for sodium channels? Psychopharmacology (Berl) 180:159–168
Nazar M, Jessa M, Plaznik A (1997) Benzodiazepine-GABAA receptor complex ligands in two models of anxiety. J Neural Transm 104:733–746
Patel JB, Malick JB (1980) Effects of isoproterenol and chlordiazepoxide on drinking and conflict behaviors in rats. Pharmacol Biochem Behav 12:819–821
Plaznik A, Palejko W, Nazar M, Jessa M (1994) Effects of antagonists at the NMDA receptor complex in two models of anxiety. Eur Neuropsychopharmacol 4:503–512
Rodgers RJ (1997) Animal models of ‘anxiety’: where next? Behav Pharmacol 8:477–496
Rodgers RJ, Davies B, Shore R (2002) Absence of anxiolytic response to chlordiazepoxide in two common background strains exposed to the elevated plus-maze: importance and implications of behavioural baseline. Genes Brain Behav 1:242–251
Rudolph U, Crestani F, Benke D, Brunig I, Benson JA, Fritschy JM, Martin JR, Bluethmann H, Mohler H (1999) Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes. Nature 401:796–800
Shekhar A, McCann UD, Meaney MJ, Blanchard DC, Davis M, Frey KA, Liberzon I, Overall KL, Shear MK, Tecott LH, Winsky L (2001) Summary of a National Institute of Mental Health workshop: developing animal models of anxiety disorders. Psychopharmacology (Berl) 157:327–339
Sieghart W (1995) Structure and pharmacology of gamma-aminobutyric acidA receptor subtypes. Pharmacol Rev 47:181–234
Soderpalm A, Blomqvist O, Soderpalm B (1995a) The yohimbine-induced anticonflict effect in the rat, Part I. Involvement of noradrenergic, serotonergic and endozepinergic(?) mechanisms. J Neural Transm Gen Sect 100:175–189
Soderpalm AK, Blomqvist O, Engel JA, Soderpalm B (1995b) Characterization of the anticonflict effect of MK-801, a non-competitive NMDA antagonist. Pharmacol Toxicol 76:122–127
Sorbera LA, Leeson PA, Silvestre J, Castaner J (2001) Pagoclone-anxiolytic GABA-A/BZD site partial agonist. Drugs Future 26:651–657
Soubrie P, de Angelis L, Boissier JR (1976) Effects of antianxiety drugs on the water intake in trained and untrained rats and mice (author's translation). Psychopharmacology (Berl) 50:41–45
Stanhope KJ, Dourish CT (1996) Effects of 5-HT1A receptor agonists, partial agonists and a silent antagonist on the performance of the conditioned emotional response test in the rat. Psychopharmacology (Berl) 128:293–303
Stocker SD, Sved AF, Stricker EM (2000) Role of renin-angiotensin system in hypotension-evoked thirst: studies with hydralazine. Am J Physiol Regul Integr Comp Physiol 279:R576–R585
Tam SW, Worcel M, Wyllie M (2001) Yohimbine: a clinical review. Pharmacol Ther 91:215–243
Teloken C, Rhoden EL, Sogari P, Dambros M, Souto CA (1998) Therapeutic effects of high dose yohimbine hydrochloride on organic erectile dysfunction. J Urol 159:122–124
Treit D (1985) Animal models for the study of anti-anxiety agents: a review. Neurosci Biobehav Rev 9:203–222
Trullas R, Skolnick P (1993) Differences in fear motivated behaviors among inbred mouse strains. Psychopharmacology (Berl) 111:323–331
Umezu T (1995) Assessment of anxiolytics (5)-Vogel-type conflict task in mice. Nihon Shinkei Seishin Yakurigaku Zasshi 15:305–314
Umezu T (1999) Effects of psychoactive drugs in the Vogel conflict test in mice. Jpn J Pharmacol 80:111–118
Uyeno ET, Davies MF, Pryor GT, Loew GH (1990) Selective effect on punished versus unpunished responding in a conflict test as the criterion for anxiogenic activity. Life Sci 47:1375–1382
van Gaalen MM, Steckler T (2000) Behavioural analysis of four mouse strains in an anxiety test battery. Behav Brain Res 115:95–106
Vanover KE, Robledo S, Huber M, Carter RB (1999) Pharmacological evaluation of a modified conflict procedure: punished drinking in non-water-deprived rats. Psychopharmacology (Berl) 145:333–341
Vogel JR, Beer B, Clody DE (1971) A simple and reliable conflict procedure for testing anti-anxiety agents. Psychopharmacologia 21:1–7
Voikar V, Koks S, Vasar E, Rauvala H (2001) Strain and gender differences in the behavior of mouse lines commonly used in transgenic studies. Physiol Behav 72:271–281
Wafford KA, Thompson SA, Thomas D, Sikela J, Wilcox AS, Whiting PJ (1996) Functional characterization of human gamma-aminobutyric acidA receptors containing the alpha 4 subunit. Mol Pharmacol 50:670–678
Whitwam JG, Amrein R (1995) Pharmacology of flumazenil. Acta Anaesthesiol Scand Suppl 108:3–14
Witkin JM, Acri JB, Gleeson S, Barrett JE (1997) Blockade of behavioral effects of bretazenil by flumazenil and ZK 93,426 in pigeons. Pharmacol Biochem Behav 56:1–7
Witkin JM, Morrow D, Li X (2004) A rapid punishment procedure for detection of anxiolytic compounds in mice. Psychopharmacology (Berl) 172:52–57
Xie ZC, Buckner E, Commissaris RL (1995) Anticonflict effect of MK-801 in rats: time course and chronic treatment studies. Pharmacol Biochem Behav 51:635–640
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Mathiasen, L., Mirza, N.R. A comparison of chlordiazepoxide, bretazenil, L838,417 and zolpidem in a validated mouse Vogel conflict test. Psychopharmacology 182, 475–484 (2005). https://doi.org/10.1007/s00213-005-0119-z
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DOI: https://doi.org/10.1007/s00213-005-0119-z