Skip to main content
SpringerLink
Log in

Pharmacological characterization of stress-induced hyperthermia in DBA/2 mice using metabotropic and ionotropic glutamate receptor ligands

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

Abstract

Rationale

Accumulating evidence suggests that drugs acting on the glutamatergic system may represent promising novel therapeutic targets for the treatment of anxiety disorders. The stress-induced hyperthermia paradigm has been used widely to model some of the physiological symptoms associated with anxiety disorders and has produced results that are predictive of clinical efficacy. We have modified this paradigm to measure the autonomic consequences of stress induced by the fear of predation in mice.

Objective

To evaluate the efficacy of several classes of metabotropic and ionotropic glutamate receptor ligands, as well as known anxiolytics and psychotropic comparators, in attenuating predatory-stress-induced hyperthermia.

Methods

Male DBA/2 mice were implanted with radiotelemetric transmitters in the peritoneal cavity to measure stress-related increases in core body temperature, following placement in a novel cage containing soiled rat shavings.

Results

Clinically active compounds such as chlordiazepoxide (5–10 mg/kg), alprazolam (0.3–3 mg/kg), and buspirone (10–30 mg/kg) exhibited an anxiolytic profile. Assessment of glutamatergic agents indicated that the mGlu1 receptor antagonist LY456236 (10–30 mg/kg), mGlu5 receptor antagonist MPEP (10–30 mg/kg), mGlu2/3 receptor agonist LY354740 (3–10 mg/kg), mGlu2 receptor potentiator LY566332 (30 and 100 mg/kg), mGlu8 receptor agonist (S)-3,4-dicarboxyphenylglycine (30–60 mg/kg), competitive NMDA receptor antagonist LY235959 (1 mg/kg), AMPA receptor antagonist GYKI-52466 (10–20 mg/kg), and glycine transporter-1 (GlyT-1) inhibitor ALX-5407 (3–10 mg/kg) dose-dependently attenuated stress-induced hyperthermia. The AMPA receptor potentiator LY451646, iGlu5 kainate receptor antagonist LY382884, glycineB receptor partial agonist d-cycloserine, and GlyT-1 inhibitor ORG-24461 were ineffective in this model.

Conclusion

Select metabotropic and ionotropic glutamate receptor ligands exhibited an anxiolytic profile, as measured by the attenuation of stress-induced hyperthermia, and may represent viable targets for the development of pharmacological treatments for anxiety-related disorders.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Abraham G, Solyom S, Csuzdi E, Berzsenyi P, Ling I, Tarnawa I, Hamori T, Pallagi I, Horvath K, Andrasi F, Kapus G, Harsing LG, Kiraly I, Patthy M, Horvath G (2000) New non competitive AMPA antagonists. Bioorg Med Chem 8:2127–2143

    Article  PubMed  CAS  Google Scholar 

  • Anthony EW, Nevins ME (1993) Anxiolytic-like effects of N-methyl-d-aspartate-associated glycine receptor ligands in the rat potentiated startle test. Eur J Pharmacol 250:317–324

    Article  PubMed  CAS  Google Scholar 

  • Atkinson BN, Bell SC, De Vivo M, Kowalski LR, Lechner SM, Ognyanov VI, Tham C-S, Tsai C, Jia J, Ashton D, Klitenick MA (2001) ALX 5407: a potent, selective inhibitor of the hGlyT1 glycine transporter. Mol Pharmacol 60:1414–1420

    PubMed  CAS  Google Scholar 

  • Bai F, Bergeron M, Nelson DL (2003) Chronic AMPA receptor potentiator (LY451646) treatment increases cell proliferation in adult rat hippocampus. Neuropharmacology 44:1013–1021

    Article  PubMed  CAS  Google Scholar 

  • Baldessarini RJ (1996) Drugs and the treatment of psychiatric disorders: psychosis and anxiety. In: Hardman JG, Limbird LE (eds) The pharmacological basis of therapeutics. McGraw-Hill, New York, pp 399–430

    Google Scholar 

  • Ball SG, Kuhn A, Wall D, Shekhar A, Goddard AW (2005) Selective serotonin reuptake inhibitor treatment for generalized anxiety disorder: a double-blind, prospective comparison between paroxetine and sertraline. J Clin Psychiatry 66:94–99

    PubMed  CAS  Google Scholar 

  • Barker MJ, Greenwood KM, Jackson M, Crowe SF (2004) Cognitive effects of long-term benzodiazepine use: a meta-analysis. CNS Drugs 18:37–48

    Article  PubMed  CAS  Google Scholar 

  • Barton ME, Peters SC, Shannon HE (2003) Comparison of the effect of glutamate receptor modulators in the 6 Hz and maximal electroshock seizure models. Epilepsy Res 56:17–26

    Article  PubMed  CAS  Google Scholar 

  • Baumbarger PJ, Muhlhauser M, Zhai J, Yang CR, Nisenbaum ES (2001) Positive modulation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors in prefrontal cortical pyramidal neurons by a novel allosteric potentiator. J Pharmacol Exp Ther 298:86–102

    PubMed  CAS  Google Scholar 

  • Belzung C, Hage WE, Moindrot N, Griebel G (2001) Behavioral and neurochemical changes following predatory stress in mice. Neuropharmacology 41:400–408

    Article  PubMed  CAS  Google Scholar 

  • Bergink V, van Megen HJ, Westenberg HG (2004) Glutamate and anxiety. Eur Neuropsychopharmacol 14:175–183

    Article  PubMed  CAS  Google Scholar 

  • Bodnoff SR, Suranyi-Cadotte B, Quirion R, Meaney MJ (1989) A comparison of the effects of diazepam versus several typical and atypical anti-depressant drugs in an animal model of anxiety. Psychopharmacology (Berl) 97:277–279

    Article  CAS  Google Scholar 

  • Bordi F, Ugolini A (1999) Group I metabotropic glutamate receptors: implications for brain diseases. Prog Neurobiol 59:55–79

    Article  PubMed  CAS  Google Scholar 

  • Borsini F, Lecci A, Volterra G, Meli A (1989) A model to measure anticipatory anxiety in mice. Psychopharmacology (Berl) 98:207–211

    Article  CAS  Google Scholar 

  • Bouwknecht JA, Paylor R (2002) Behavioral and physiological mouse assays for anxiety: a survey in nine mouse strains. Behav Brain Res 136:489–501

    Article  PubMed  Google Scholar 

  • Briese E, Cabanac M (1991) Stress hyperthermia: physiological arguments that it is a fever. Physiol Behav 49:1153–1157

    Article  PubMed  CAS  Google Scholar 

  • Brodkin J, Busse C, Sukoff SJ, Varney MA (2002) Anxiolytic-like activity of the mGluR5 antagonist MPEP: a comparison with diazepam and buspirone. Pharmacol Biochem Behav 73:359–366

    Article  PubMed  CAS  Google Scholar 

  • Bubser M, Keseberg U, Notz PK, Schmidt WJ (1992) Differential behavioural and neurochemical effects of competitive and non-competitive NMDA receptor antagonists in rats. Eur J Pharmacol 229:75–82

    Article  PubMed  CAS  Google Scholar 

  • Carvalho-Netto EF, Nunes-de-Souza RL (2004) Use of the elevated T-maze to study anxiety in mice. Behav Brain Res 148:119–132

    Article  PubMed  CAS  Google Scholar 

  • Delle-Chiaie R, Pancheri P, Casacchia M, Stratta P, Kotzalidis G, Zibellini M (1995) Assessment of the efficacy of buspirone in patients affected by generalized anxiety disorder, shifting to buspirone from prior treatment with lorazepam: a placebo-controlled, double-blind study. J Clin Psychopharmacol 15:12–19

    Article  PubMed  CAS  Google Scholar 

  • Dielenberg RA, Carrive P, McGregor IS (2001) The cardiovascular and behavioral response to cat odor in rats: unconditioned and conditioned effects. Brain Res 897:228–237

    Article  PubMed  CAS  Google Scholar 

  • Dunn RW, Corbett R, Fielding S (1989) Effects of 5-HT1A receptor agonists and NMDA receptor antagonists in the social interaction test and the elevated plus maze. Eur J Pharmacol 169:1–10

    Article  PubMed  CAS  Google Scholar 

  • Fanselow MS, Kim JJ (1994) Acquisition of contextual Pavlovian fear conditioning is blocked by application of an NMDA receptor antagonist d,l-2-amino-5-phosphonovaleric acid to the basolateral amygdala. Behav Neurosci 108:210–212

    Article  PubMed  CAS  Google Scholar 

  • Fendt M, Schmid S (2002) Metabotropic glutamate receptors are involved in amygdaloid plasticity. Eur J Neurosci 15:1535–1541

    Article  PubMed  Google Scholar 

  • Fricchione G (2004) Generalized anxiety disorder. N Engl J Med 351:675–685

    Article  PubMed  CAS  Google Scholar 

  • Gasparini F, Lingenhohl K, Stoehr N, Flor PJ, Heinrich M, Vranesic I, Biollaz M, Allgeier H, Heckendorn R, Urwyler S, Varney MA, Johnson EC, Hess SD, Rao SP, Sacaan AI, Santori EM, Velicelebi G, Kuhn R (1999) 2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist. Neuropharmacology 38:1493–1503

    Article  PubMed  CAS  Google Scholar 

  • Greenberg PE, Sisitsky T, Kessler RC, Finkelstein SN, Berndt ER, Davidson JRT, Ballenger JC, Fyer AJ (1999) The economic burden of anxiety disorders in the 1990s. J Clin Psychiatry 60:427–435

    PubMed  CAS  Google Scholar 

  • Griebel G, Blanchard DC, Agnes RS, Blanchard RJ (1995) Differential modulation of antipredator defensive behavior in Swiss–Webster mice following acute or chronic administration of imipramine and fluoxetine. Psychopharmacology (Berl) 120:57–66

    Article  CAS  Google Scholar 

  • Grillon C, Cordova J, Levine LR, Morgan CA (2003) Anxiolytic effects of a novel group II metabotropic glutamate receptor agonist (LY354740) in the fear-potentiated startle paradigm in humans. Psychopharmacology (Berl) 168:446–454

    Article  CAS  Google Scholar 

  • Gudex C (1991) Adverse effects of benzodiazepines. Soc Sci Med 33:587–596

    Article  PubMed  CAS  Google Scholar 

  • Harsing LG, Gacsalyi I, Szabo G, Schmidt E, Sziray N, Sebban C, Tesolin-Decros B, Matyus P, Egyed A, Spedding M, Levay G (2003) The glycine transporter-1 inhibitors NFPS and Org 24461: a pharmacological study. Pharmacol Biochem Behav 74:811–825

    Article  PubMed  CAS  Google Scholar 

  • Helton DR, Tizzano JP, Monn JA, Schoepp DD, Kallman MJ (1998) Anxiolytic and side-effect profile of LY354740: a potent, highly selective, orally active agonist for group II metabotropic glutamate receptors. J Pharmacol Exp Ther 284:651–660

    PubMed  CAS  Google Scholar 

  • Heyden JAM, Zethof TJJ, Olivier B (1997) Stress-induced hyperthermia in singly housed mice. Physiol Behav 62:463–470

    Article  PubMed  Google Scholar 

  • Javitt DC (2004) Glutamate as a therapeutic target in psychiatric disorders. Mol Psychiatry 9:984–997, 979

    Article  PubMed  CAS  Google Scholar 

  • Johnson MP, Barda D, Britton TC, Emkey R, Hornback WJ, Jagdmann GE, McKinzie DL, Nisenbaum ES, Tizzano JP, Schoepp DD (2005) Metabotropic glutamate 2 receptor potentiators: receptor modulation, frequency-dependent synaptic activity, and efficacy in preclinical anxiety and psychosis model(s). Psychopharmacology (Berl) 179:271–283

    Article  CAS  Google Scholar 

  • Karcz-Kubicha M, Jessa M, Nazar M, Plaznik A, Hartmann S, Parsons CG, Danysz W (1997) Anxiolytic activity of glycine-B antagonists and partial agonists: no relation to intrinsic activity in the patch clamp. Neuropharmacology 36:1355–1367

    Article  PubMed  CAS  Google Scholar 

  • Kehne JH, McCloskey TC, Baron BM, Chi EM, Harrison BL, Whitten JP, Palfreyman MG (1991) NMDA receptor complex antagonists have potential anxiolytic effects as measured with separation-induced ultrasonic vocalizations. Eur J Pharmacol 193:283–292

    Article  PubMed  CAS  Google Scholar 

  • Kinney GG, Sur C, Burno M, Mallorga PJ, Williams JB, Figueroa DJ, Wittmann M, Lemaire W, Conn PJ (2003) The glycine transporter type 1 inhibitor N-[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl]sarcosine potentiates NMDA receptor-mediated responses in vivo and produces an antipsychotic profile in rodent behavior. J Neurosci 23:7586–7591

    PubMed  CAS  Google Scholar 

  • Klodzinska A, Chojnacka-Wojcik E (2000) Anticonflict effect of the glycineB receptor partial agonist, d-cycloserine, in rats. Pharmacological analysis. Psychopharmacology (Berl) 152:224–228

    Article  CAS  Google Scholar 

  • Klodzinska A, Chojnacka-Wojcik E, Palucha A, Branski P, Popik P, Pilc A (1999) Potential anti-anxiety, anti-addictive effects of LY354740, a selective group II glutamate metabotropic receptor agonist in animal models. Neuropharmacology 38:1831–1839

    Article  PubMed  CAS  Google Scholar 

  • Kotlinska J, Liljequist S (1998) The putative AMPA receptor antagonist, LY326325, produces anxiolytic-like effects without altering locomotor activity in rats. Pharmacol Biochem Behav 60:119–124

    Article  PubMed  CAS  Google Scholar 

  • Lanthorn TH (1994) d-Cycloserine: agonist turned antagonist. Amino Acids 6:247–260

    Article  CAS  Google Scholar 

  • Li L, Tomlinson R, Wang Y, Tsui H-CT, Chamberlain M-J, Johnson MP, Baez M, Vannieuwenhze MS, Zia-Ebrahimi M, Hong EJ, Schkeryantz JM, Monn JA, Porter WJ, Baker SR, Owton WM, Clark BP, Kingston AE (2002) A novel series of potent and selective non-competitive antagonists of metabotropic glutamate receptor 1. Neuropharmacology 43:295

    Google Scholar 

  • Linden A-M, Johnson BG, Peters SC, Shannon HE, Tian M, Wang Y, Yu JL, Koster A, Baez M, Schoepp DD (2002) Increased anxiety-related behavior in mice deficient for metabotropic glutamate 8 (mGlu8) receptor. Neuropharmacology 43:251–259

    Article  PubMed  CAS  Google Scholar 

  • Linden A-M, Bergeron M, Baez M, Schoepp DD (2003) Systemic administration of the potent mGlu8 receptor agonist (S)-3,4-DCPG induces c-Fos in stress-related brain regions in wild-type, but not mGlu8 receptor knockout mice. Neuropharmacology 45:473–483

    Article  PubMed  CAS  Google Scholar 

  • Linden A-M, Greene SJ, Bergeron M, Schoepp DD (2004) Anxiolytic activity of the mGlu2/3 receptor agonist LY354740 on the elevated plus maze is associated with the suppression of stress-induced c-Fos in the hippocampus and increases in c-Fos induction in several other stress-sensitive brain regions. Neuropsychopharmacology 29:502–513

    Article  PubMed  CAS  Google Scholar 

  • Marazziti D, di Muro A, Castrogiovanni P (1992) Psychological stress and body temperature changes in humans. Physiol Behav 52:393–395

    Article  PubMed  CAS  Google Scholar 

  • Marek GJ (2004) Metabotropic glutamate 2/3 receptors as drug targets. Curr Opin Pharmacol 4:18–22

    Article  PubMed  CAS  Google Scholar 

  • Merali Z, Levac C, Anisman H (2003) Validation of a simple, ethologically relevant paradigm for assessing anxiety in mice. Biol Psychiatry 54:552–565

    Article  PubMed  Google Scholar 

  • Monn JA, Valli MJ, Massey SM, Wright RA, Salhoff CR, Johnson BG, Howe T, Alt CA, Rhodes GA, Robey RL, Griffey KR, Tizzano JP, Kallman MJ, Helton DR, Schoepp DD (1997) Design, synthesis, and pharmacological characterization of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740): a potent, selective, and orally active group 2 metabotropic glutamate receptor agonist possessing anticonvulsant and anxiolytic properties. J Med Chem 40:528–537

    Article  PubMed  CAS  Google Scholar 

  • Monohan JB, Corpus VM, Hood WF, Thomas JW, Compton RP (1989) Characterization of a [3H]glycine recognition site as a modulatory site of the N-methyl-d-aspartate receptor complex. J Neurochem 53:370–375

    Article  PubMed  Google Scholar 

  • Olivier B, Zethof T, Pattij T, van Boogaert M, van Oorschot R, Leahy C, Oosting R, Bouwknecht A, Veening J, van der Gugten J, Groenink L (2003) Stress-induced hyperthermia and anxiety: pharmacological validation. Eur J Pharmacol 463:117–132

    Article  PubMed  CAS  Google Scholar 

  • O'Neill MJ, Bond A, Ornstein PL, Ward MA, Hicks CA, Hoo K, Bleakman D, Lodge D (1998) Decahydroisoquinolines: novel competitive AMPA/kainate antagonists with neuroprotective effects in global cerebral ischaemia. Neuropharmacology 37:1211–1222

    Article  PubMed  Google Scholar 

  • Parsons CG, Danysz W, Quack G (1998) Glutamate in CNS disorders as a target for drug development: an update. Drug News Perspect 11:523–579

    Article  PubMed  CAS  Google Scholar 

  • Popoli M, Gennarelli M, Racagni G (2002) Modulation of synaptic plasticity by stress and antidepressants. Bipolar Disord 4:166–182

    Article  PubMed  CAS  Google Scholar 

  • Quirk JC, Nisenbaum ES (2002) LY404187: a novel positive allosteric modulator of AMPA receptors. CNS Drug Rev 8:255–282

    PubMed  CAS  Google Scholar 

  • Sarro G, Gratteri S, Naccari F, Pasculli MP, Sarro A (2000) Influence of d-cycloserine on the anticonvulsant activity of some antiepileptic drugs against audiogenic seizures in DBA/2 mice. Epilepsy Res 40:109–121

    Article  PubMed  Google Scholar 

  • Schmitt U, Walkhofer S, Weigelt T, Hiemke C (2002) Free-choice ethanol consumption under the influence of GABAergic drugs in rats. Alcohol Clin Exp Res 26:457–462

    Article  PubMed  CAS  Google Scholar 

  • Schoepp DD (2001) Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system. J Pharmacol Exp Ther 299:12–20

    PubMed  CAS  Google Scholar 

  • Schoepp DD, Wright RA, Levine LR, Gaydos B, Potter WZ (2003) LY354740, an mGlu2/3 receptor agonist as a novel approach to treat anxiety/stress. Stress 6:189–197

    Article  PubMed  CAS  Google Scholar 

  • Shekhar A, Keim SR (2000) LY354740, a potent group II metabotropic glutamate receptor agonist prevents lactate-induced panic-like response in panic-prone rats. Neuropharmacology 39:1139–1146

    Article  PubMed  CAS  Google Scholar 

  • Spooren WPJM, Vassout A, Neijt HC, Kuhn R, Gasparini F, Roux S, Porsolt RD, Gentsch C (2000) Anxiolytic-like effects of the prototypical metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)pyridine in rodents. J Pharmacol Exp Ther 295:1267–1275

    PubMed  CAS  Google Scholar 

  • Spooren WPJM, Schoeffter P, Gasparini F, Kuhn R, Gentsch C (2002) Pharmacological and endocrinological characterisation of stress-induced hyperthermia in singly housed mice using classical and candidate anxiolytics (LY314582, MPEP, and NKP608). Eur J Pharmacol 435:161–170

    Article  PubMed  CAS  Google Scholar 

  • Spowart-Manning L, Staay FJ (2004) The T-maze continuous alternation task for assessing the effects of putative cognition enhancers in the mouse. Behav Brain Res 151:37–46

    Article  PubMed  CAS  Google Scholar 

  • Thomas NK, Wright RA, Howson PA, Kingston AE, Schoepp DD, Jane DE (2001) (S)-3,4-DCPG, a potent and selective mGlu8a receptor agonist, activates metabotropic glutamate receptors on primary afferent terminals in the neonatal rat spinal cord. Neuropharmacology 40:311–318

    Article  PubMed  CAS  Google Scholar 

  • Vanover KE, Suruki M, Robledo S, Huber M, Wieland S, Lan NC, Gee KW, Wood PL, Carter RB (1999) Positive allosteric modulators of the GABAA receptor: differential interaction of benzodiazepines and neuroactive steroids with ethanol. Psychopharmacology (Berl) 141:77–82

    Article  CAS  Google Scholar 

  • Varty GB, Grilli M, Forlani A, Fredduzzi S, Grzelak ME, Guthrie DH, Hodgson RA, Lu SX, Nicolussi E, Pond AJ, Parker EM, Hunter JC, Higgins GA, Reggiani A, Bertorelli R (2005) The antinociceptive and anxiolytic-like effects of the metabotropic glutamate receptor 5 (mGluR5) antagonists, MPEP and MTEP, and the mGluR1 antagonist, LY456236, in rodents: a comparison of efficacy and side-effect profiles. Psychopharmacology (Berl) 179:207–217

    Google Scholar 

  • Zethof TJJ, Heyden JAM, Tolboom JTBM, Olivier B (1995) Stress-induced hyperthermia as a putative anxiety model. Eur J Pharmacol 294:125–135

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Neuroscience Discovery Research, Eli Lilly & Company, Indianapolis, IN, 46285, USA

    Linda M. Rorick-Kehn, John C. Hart & David L. McKinzie

Authors
  1. Linda M. Rorick-Kehn
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John C. Hart
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David L. McKinzie
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David L. McKinzie.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rorick-Kehn, L.M., Hart, J.C. & McKinzie, D.L. Pharmacological characterization of stress-induced hyperthermia in DBA/2 mice using metabotropic and ionotropic glutamate receptor ligands. Psychopharmacology 183, 226–240 (2005). https://doi.org/10.1007/s00213-005-0169-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-005-0169-2

Keywords

Search

Navigation