Skip to main content
SpringerLink
Log in

Discriminative stimulus properties of a new anxiolytic, DN-2327, in rats

  • Original Investigations
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

In an operant learning lever-pressing procedure on an FR10 schedule of milk reinforcement, male Wistar rats were trained to discriminate between saline and 3 mg/kg IP DN-2327, a new anxiolytic which acts on benzodiazepine receptors, 3 mg/kg IP diazepam or 15 mg/kg IP pentylenetetrazol (PTZ). More than 80% appropriate lever responding was established after 27, 38 and 44 daily training sessions with DN-2327, diazepam and PTZ, respectively, as the training drug. Although rats trained with DN-2327 dose-dependently generalized to various doses of DN-2327 and diazepam, the cue of DN-2327 was more potent than that of diazepam: ED50 values of DN-2327 and diazepam for stimulus generalization were 0.30 and 0.66 mg/kg, respectively. These animals partially generalized to pentobarbital (1–10 mg/kg) but did not generalize to buspirone (0.1–10 mg/kg). Rats trained with diazepam dose-dependently generalized to various doses of DN-2327, diazepam and pentobarbital with ED50 values of 0.51, 0.47 and 4.5 mg/kg, respectively, but did not generalize to buspirone. In rats trained with PTZ, DN-2327 and diazepam antagonized the discriminative stimulus produced by 15 mg/kg PTZ in a dose-dependent manner with ED50 values of 0.27 and 0.83 mg/kg, respectively, but buspirone neither antagonized nor was able to substitute for the PTZ-induced stimulus. The cue of DN-2327 was antagonized by flumazenil dose-dependently as was that of diazepam. Diazepam and pentobarbital reduced the total number of responses in all animals at 10 mg/kg, and buspirone did so at more than 3 mg/kg, while DN-2327 did not affect the total number of responses from 0.1 to 10 mg/kg. In conclusion, the cue of DN-2327 is similar to and more effective than that of diazepam; moreover, it is quite different from that of buspirone. In addition, the similarity of the interoceptive stimuli of DN-2327 and diazepam may suggest that they are not related to muscle relaxant and sedative properties, since the two drugs differ in this respect.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Andrews JS, Stephens DN (1990) Drug discrimination models in anxiety and depression. Pharmacol Ther 47:267–280

    Google Scholar 

  • Andrews JS, Stephens DN (1991) Discriminative stimulus properties of the benzodiazepine receptor partial agonistβ-carbolines abecarnil and ZK95962: a comparison with chlordiazepoxide. Behav Pharmacol 2:171–185

    Google Scholar 

  • Ator NA, Griffiths RR (1983) Lorazepam and pentobarbital drug discrimination in baboons: cross-drug generalization and interaction with Ro15-1788. J Pharmacol Exp Ther 226:776–782

    Google Scholar 

  • Ator NA, Griffiths RR (1986) Discriminative stimulus effects of atypical anxiolytics in baboons and rats. J Pharmacol Exp Ther 237:393–403

    Google Scholar 

  • Ator NA, Cook JM, Griffiths RR (1989) Drug discrimination in pentylenetetrazol-trained baboons: generalization to buspirone andβ-carboline-3-carboxylic acid ethyl ester but not lorazepam or pentobarbital. Drug Dev Res 16:257–267

    Google Scholar 

  • Bernard PS, Bennett DA, Pastor G, Yokoyama N, Liebman JM (1985) CGS9896: agonist-antagonist benzodiazepine receptor activity revealed by anxiolytic, anticonvulsant and muscle relaxation assessment in rodents. J Pharmacol Exp Ther 235:98–105

    Google Scholar 

  • Charney DS, Heninger GR, Redmond DE (1983) Yohimbine-induced anxiety and increased noradrenergic function in humans: effects of diazepam and clonidine. Life Sci 33:19–29

    Google Scholar 

  • Colpaert FC, Desmedt LKC, Janssen PAJ (1976) Discriminative stimulus properties of benzodiazepines, barbiturates and pharmacologically related drugs: relation to some intrinsic and anticonvulsant effects. Eur J Pharmacol 37:113–123

    Google Scholar 

  • Cooper SJ, Kirkham TC, Estall LB (1987) Pyrazoloquinolines: second generation benzodiazepine receptor ligands have heterogeneous effects. TIPS 8:180–184

    Google Scholar 

  • Critchley MAE, Handley SL (1987) 5-HT1A ligand effects in the X-maze anxiety test. Br J Pharmacol 92:660P

    Google Scholar 

  • Extance K, Goudie AJ (1981) Inter-animal olfactory cues in operant drug discrimination procedures in rats. Psychopharmacology 73:363–371

    Google Scholar 

  • File SE, Lister RG (1984) Do the reductions in social interaction produced by picrotoxin and pentylenetetrazole indicate anxiogenic actions? Neuropharmacology 23:793–796

    Google Scholar 

  • Finney DJ (1944) The application of probit analysis to the results of mental tests. Psychometrika 9:31–39

    Google Scholar 

  • Gammans RE, Mayol RF, Eison MS (1983) Concentration of buspirone and 1-pyrimidinyl-piperazine, a metabolite, in rat brain. Fed Proc 42:377

    Google Scholar 

  • Garcha HS, Rose IC, Stolerman IP (1985) Midazolam cue in rats: generalization tests with anxiolytic and other drugs. Psychopharmacology 87:233–237

    Google Scholar 

  • Gardner CR (1989) Discriminative stimulus properties of CL218872 and chlordiazepoxide in the rat. Pharmacol Biochem Behav 34:711–715

    Google Scholar 

  • Gee KW, Brinton RE, Yamamura HI (1983) CL218872 antagonism of diazepam-induced loss of righting reflex: evidence for partial agonistic activity at the benzodiazepine receptor. Life Sci 32:1037–1040

    Google Scholar 

  • Gower AJ (1986) In vivoα 2-adrenoceptor antagonist activity of buspirone and its metabolite 1-(2-pyrimidyl) piperazine (1-PP) in the rat. Br J Pharmacol 89:726P

    Google Scholar 

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

    Google Scholar 

  • Handley SL, Mithani S (1984b) Effects on punished responding of drugs acting at alpha-adrenoceptors. Br J Pharmacol 82:341

    Google Scholar 

  • Hashimoto T, Wada T, Fukuda N (1990) Behavioral and EEG effects of a novel anxioselective anxiolytic, DN-2327, in cats. 17th C.I.N.P. Congress Meeting Abstracts 1:179p

  • Haug T (1983) Neuropharmacological specificity of the diazepam stimulus complex: effects of agonists and antagonists. Eur J Pharmacol 93:221–227

    Google Scholar 

  • Haug T, Gotestam KG (1982) The diazepam stimulus complex: specificity in a rat model. Eur J Pharmacol 80:225–230

    Google Scholar 

  • Hendry JS, Balster RL, Rosecrans JA (1983) Discriminative stimulus properties of buspirone compared to central nervous system depressants in rats. Pharmacol Biochem Behav 19:97–101

    Google Scholar 

  • Herling S, Shannon HE (1982) Ro15-1788 antagonizes the discriminative stimulus effects of diazepam in rats but not similar effects of pentobarbital. Life Sci 31:2105–2112

    Google Scholar 

  • Holmberg G, Gershon S (1961) Autonomic and psychic effects of yohimbine hydrochloride. Psychopharmacology 2:93–106

    Google Scholar 

  • Johansson JO, Jarbe TUC (1975) Diazepam as a discriminative cue: its antagonism by bemegride. Eur J Pharmacol 30:372–375

    Google Scholar 

  • Johnston AL, File SE (1989) Yohimbine's anxiogenic action: evidence for noradrenergic and dopaminergic sites. Pharmacol Biochem Behav 32:151–156

    Google Scholar 

  • Lal H, Emmett-Oglesby MW (1983) Behavioral analogues of anxiety: animal models. Neuropharmacology 22:1432–1441

    Google Scholar 

  • Lal H, Fielding S (1984) Antagonism of discriminative stimuli produced by anxiogenic drugs as a novel approach to bioassay anxiolytics. Drug Dev Res 4:3–21

    Google Scholar 

  • Moser PC (1989) An evaluation of the elevated plus-maze test using the novel anxiolytic buspirone. Psychopharmacology 99:48–53

    Google Scholar 

  • Overton DA (1976) Discriminable effects of benzodiazepines. Psychopharmacol Commun 2:339–343

    Google Scholar 

  • Pellow S, Chopin P, File SE, Briley M (1985a) 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

    Google Scholar 

  • Pellow S, Chopin P, File SE (1985b) Are the anxiogenic effects of yohimbine mediated by its action at benzodiazepine receptors? Neurosci Lett 55:5–9

    Google Scholar 

  • Prado de Carvaiho L, Venault P, Rossier J, Chapouthier G (1983) Anxiogenic properties of convulsive agents. Soc Neurosci Abstr 9:128

    Google Scholar 

  • Rodin EA, Calhoun HD (1970) Metrazol tolerance in a “normal” volunteer population. J Nerv Ment Dis 150:438–450

    Google Scholar 

  • Sanger DJ, Zivkovic B (1987) Discriminative stimulus properties of chlordiazepoxide and zolpidem. Agonist and antagonist effects of CGS9896 and ZK91296. Neuropharmacology 26:499–505

    Google Scholar 

  • Sanger DJ, Joly D, Zivkovic B (1985) Behavioral effects of non-benzodiazepine anxiolytic drugs: a comparison of CGS9896 and zopiclone with chlordiazepoxide. J Pharmacol Exp Ther 232:831–837

    Google Scholar 

  • Shannon HE, Davis LS (1984) CGS8216 non-competitively antagonizes the discriminative effects of diazepam in rats. Life Sci 34:2589–2596

    Google Scholar 

  • Shannon HE, Herling S (1983) Discriminative stimulus effects of diazepam in rats: Evidence for a maximal effect. J Pharmacol Exp Ther 227:160–166

    Google Scholar 

  • Shearman GT, Lal H (1979) Discriminative stimulus properties of pentylenetetrazol and bemegride: some generalization and antagonism tests. Psychopharmacology 64:315–319

    Google Scholar 

  • Shearman GT, Lal H (1980) Generalization and antagonism studies with convulsant, gabaergic and anticonvulsant drugs in rats trained to discriminate pentylenetetrazol from saline. Neuropharmacology 19:473

    Google Scholar 

  • Spealman RD (1985) Discriminative stimulus effects of midazolam in squirrel monkeys: comparison with other drugs and antagonism by Ro15-1788. J Pharmacol Exp Ther 235:456–462

    Google Scholar 

  • Stephens DN, Shearman GT, Kehr W (1984) Discriminative stimulus properties ofβ-carbolines characterized as agonists and inverse agonists at central benzodiazepine receptors. Psychopharmacology 83:233–239

    Google Scholar 

  • Stolerman IP, Garcha HS, Rose IC (1986) Midazolam cue in rats: effects of Ro15-1788 and picrotoxin. Psychopharmacology 89:183–188

    Google Scholar 

  • Wada T, Fukuda N (1991a) Pharmacologic profile of a new anxiolytic, DN-2327: effect of Ro15-1788 and interaction with diazepam in rodents. Psychopharmacology 103:314–322

    Google Scholar 

  • Wada T, Fukuda N (1991b) Effects of DN-2327, a new anxiolytic, diazepam and buspirone on exploratory activity of the rat in an elevated plus-maze. Psychopharmacology 104:444–450

    Google Scholar 

  • Wada T, Fukuda N (1992) Effect of a new anxiolytic, DN-2327, on learning and memory in rats. Pharmacol Biochem Behav 41 (in press)

  • Wada T, Nakajima R, Kurihara E, Narumi S, Masuoka Y, Goto G, Saji Y, Fukuda N (1989) Pharmacologic characterization of a novel non-benzodiazepine selective anxiolytic, DN-2327. Jpn J Pharmacol 49:337–349

    Google Scholar 

  • Wilson DE, Bennett DA (1989) Pentylenetetrazol discriminative stimuli are selective for identifying benzodiazepine receptor modulating agents. Drug Dev Res 17:237–243

    Google Scholar 

  • Wood PL, Loo P, Braunwalder A, Yokoyama N, Cheney DL (1984) In vitro characterization of benzodiazepine receptor agonists, antagonists, inverse agonists and agonist/antagonists. J Pharmacol Exp Ther 231:572–576

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pharmaceutical Research Laboratories I, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., 17-85, Jusohonmachi 2-chome, Yodogawa-ku, 532, Osaka, Japan

    Takeo Wada & Naohisa Fukuda

Authors
  1. Takeo Wada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Naohisa Fukuda
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wada, T., Fukuda, N. Discriminative stimulus properties of a new anxiolytic, DN-2327, in rats. Psychopharmacology 110, 280–286 (1993). https://doi.org/10.1007/BF02251282

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02251282

Key words

Search

Navigation