Skip to main content
SpringerLink
Log in

Stimulation of the metabotropic glutamate 2/3 receptor attenuates social novelty discrimination deficits induced by neonatal phencyclidine treatment

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

Abstract

Rationale

Glutamatergic mechanisms are implicated in psychiatric disorders such as schizophrenia. Modulation of glutamatergic neurotransmission via stimulation of the metabotropic glutamate 2/3 receptors (mGluR2/3) has been shown to reverse a number of behavioral effects of NMDA receptor antagonists thus indicating potential antipsychotic activity of mGluR2/3 agonists.

Objectives

The present study aimed to evaluate the effects of LY-354740 (mGluR2/3 agonist) and LY-487379 (mGluR2 potentiator) on social novelty discrimination in male Wistar rats that were treated with PCP (10 mg/kg, s.c.) on postnatal days 7, 9, and 11.

Materials and methods

During each test session (twice a week, postnatal days 70–100), an adult experimental rat was presented with a juvenile, untreated rat (4 weeks old) for a period of 30 min. At the end of this period, a second (novel) juvenile rat was introduced for 5 min.

Results

Adult rats spent more time exploring the novel than the familiar juvenile. This capacity for social novelty discrimination was impaired in rats that received neonatal PCP treatment and the impaired discrimination could be reversed by acute treatment with antipsychotic drugs such as clozapine (0.3–3 mg/kg) and the glycine transporter GlyT1 inhibitor SSR-504734 (1–10 mg/kg). Acute pretreatment with LY-354740 (1–10 mg/kg) or LY-487379 (3–30 mg/kg) facilitated social discrimination in rats with PCP administration history without having appreciable effects in controls and without affecting total time spent in social interaction.

Conclusions

These results suggest that targeting glutamatergic functions may reverse long-term developmental cognitive deficits produced by PCP.

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

Similar content being viewed by others

References

  • Andersen JD, Pouzet B (2004) Spatial memory deficits induced by perinatal treatment of rats with PCP and reversal effect of d-serine. Neuropsychopharmacology 29:1080–1090

    Article  PubMed  CAS  Google Scholar 

  • Aultman JM, Moghaddam B (2001) Distinct contributions of glutamate and dopamine receptors to temporal aspects of rodent working memory using a clinically relevant task. Psychopharmacology (Berl) 153:353–364

    Article  CAS  Google Scholar 

  • Becker A, Grecksch G (2003) Haloperidol and clozapine affect social behaviour in rats postnatally lesioned in the ventral hippocampus. Pharmacol Biochem Behav 76:1–8

    Article  PubMed  CAS  Google Scholar 

  • Brooks WJ, Petit TL, Leboutillier JC (1997a) Effect of chronic administration of NMDA antagonists on synaptic development. Synapse 26:104–113

    Article  PubMed  CAS  Google Scholar 

  • Brooks WJ, Weeks AC, Leboutillier JC, Petit TL (1997b) Altered NMDA sensitivity and learning following chronic developmental NMDA antagonism. Physiol Behav 62:955–962

    Article  PubMed  CAS  Google Scholar 

  • Bruins Slot LA, Kleven MS, Newman-Tancredi A (2005) Effects of novel antipsychotics with mixed D(2) antagonist/5-HT(1A) agonist properties on PCP-induced social interaction deficits in the rat. Neuropharmacology 49:996–1006

    Article  PubMed  CAS  Google Scholar 

  • Cartmell J, Schoepp DD (2000) Regulation of neurotransmitter release by metabotropic glutamate receptors. J Neurochem 75:889–907

    Article  PubMed  CAS  Google Scholar 

  • Cartmell J, Monn JA, Schoepp DD (1999) The metabotropic glutamate 2/3 receptor agonists LY354740 and LY379268 selectively attenuate phencyclidine versus d-amphetamine motor behaviors in rats. J Pharmacol Exp Ther 291:161–170

    PubMed  CAS  Google Scholar 

  • Chen L, Muhlhauser M, Yang CR (2003) Glycine transporter-1 blockade potentiates NMDA-mediated responses in rat prefrontal cortical neurons in vitro and in vivo. J Neurophysiol 89:691–703

    Article  PubMed  CAS  Google Scholar 

  • Clancy B, Darlington RB, Finlay BL (2001) Translating developmental time across mammalian species. Neuroscience 105:7–17

    Article  PubMed  CAS  Google Scholar 

  • Clark M, Johnson BG, Wright RA, Monn JA, Schoepp DD (2002) Effects of the mGlu2/3 receptor agonist LY379268 on motor activity in phencyclidine-sensitized rats. Pharmacol Biochem Behav 73:339–346

    Article  PubMed  CAS  Google Scholar 

  • Conn PJ, Pin JP (1997) Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol 37:205–237

    Article  PubMed  CAS  Google Scholar 

  • Corbett R, Hartman H, Kerman LL, Woods AT, Strupczewski JT, Helsley GC, Conway PC, Dunn RW (1993) Effects of atypical antipsychotic agents on social behavior in rodents. Pharmacol Biochem Behav 45:9–17

    Article  PubMed  CAS  Google Scholar 

  • Depoortere R, Dargazanli G, Estenne-Bouhtou G, Coste A, Lanneau C, Desvignes C, Poncelet M, Heaulme M, Santucci V, Decobert M, Cudennec A, Voltz C, Boulay D, Terranova JP, Stemmelin J, Roger P, Marabout B, Sevrin M, Vige X, Biton B, Steinberg R, Francon D, Alonso R, Avenet P, Oury-Donat F, Perrault G, Griebel G, George P, Soubrie P, Scatton B (2005) Neurochemical, electrophysiological and pharmacological profiles of the selective inhibitor of the glycine transporter-1 SSR504734, a potential new type of antipsychotic. Neuropsychopharmacology 30:1963–1985

    Article  PubMed  CAS  Google Scholar 

  • Engelmann M, Wotjak CT, Landgraf R (1995) Social discrimination procedure: an alternative method to investigate juvenile recognition abilities in rats. Physiol Behav 58:315–321

    Article  PubMed  CAS  Google Scholar 

  • Eulenburg V, Armsen W, Betz H, Gomeza J (2005) Glycine transporters: essential regulators of neurotransmission. Trends Biochem Sci 30:325–333

    Article  PubMed  CAS  Google Scholar 

  • Galici R, Echemendia NG, Rodriguez AL, Conn PJ (2005) A selective allosteric potentiator of metabotropic glutamate (mGlu) 2 receptor has effects similar to an orthosteric mGlu2/3 receptor agonist in mouse models predictive of antipsychotic activity. J Pharmacol Exp Ther 315:1181–1187

    Article  PubMed  CAS  Google Scholar 

  • Goff DC, Coyle JT (2001) The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am J Psychiatry 158:1367–1377

    Article  PubMed  CAS  Google Scholar 

  • Goldberg TE, Gold JM (1995) Neurocognitive deficits in schizophrenia. In: Hirsch SR, Weinberger DR (eds) Schizophrenia. Blackwell Science, pp 146–162

  • Higgins GA, Ballard TM, Kew JN, Richards JG, Kemp JA, Adam G, Woltering T, Nakanishi S, Mutel V (2004) Pharmacological manipulation of mGlu2 receptors influences cognitive performance in the rodent. Neuropharmacology 46:907–917

    Article  PubMed  CAS  Google Scholar 

  • Homayoun H, Jackson ME, Moghaddam B (2005) Activation of metabotropic glutamate 2/3 receptors reverses the effects of NMDA receptor hypofunction on prefrontal cortex unit activity in awake rats. J Neurophysiol 93:1989–2001

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Javitt DC, Balla A, Sershen H, Lajtha A (1999) A.E. Bennett Research Award. Reversal of phencyclidine-induced effects by glycine and glycine transport inhibitors. Biol Psychiatry 45:668–679

    Article  PubMed  CAS  Google Scholar 

  • Javitt DC, Silipo G, Cienfuegos A, Shelley AM, Bark N, Park M, Lindenmayer JP, Suckow R, Zukin SR (2001) Adjunctive high-dose glycine in the treatment of schizophrenia. Int J Neuropsychopharmacol 4:385–391

    Article  PubMed  CAS  Google Scholar 

  • Johnson MP, Baez M, Jagdmann GE Jr, Britton TC, Large TH, Callagaro DO, Tizzano JP, Monn JA, Schoepp DD (2003) Discovery of allosteric potentiators for the metabotropic glutamate 2 receptor: synthesis and subtype selectivity of N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2- trifluoroethylsulfonyl)pyrid-3-ylmethylamine. J Med Chem 46:3189–3192

    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 

  • Lahti AC, Koffel B, LaPorte D, Tamminga CA (1995) Subanesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacology 13:9–19

    Article  PubMed  CAS  Google Scholar 

  • Le Pen G, Kew J, Alberati D, Borroni E, Heitz MP, Moreau JL (2003) Prepulse inhibition deficits of the startle reflex in neonatal ventral hippocampal-lesioned rats: reversal by glycine and a glycine transporter inhibitor. Biol Psychiatry 54:1162–1170

    Article  PubMed  CAS  Google Scholar 

  • Lipska BK, Weinberger DR (2000) To model a psychiatric disorder in animals: schizophrenia as a reality test. Neuropsychopharmacology 23:223–239

    Article  PubMed  CAS  Google Scholar 

  • Martina M, Gorfinkel Y, Halman S, Lowe JA, Periyalwar P, Schmidt CJ, Bergeron R (2004) Glycine transporter type 1 blockade changes NMDA receptor-mediated responses and LTP in hippocampal CA1 pyramidal cells by altering extracellular glycine levels. J Physiol 557:489–500

    Article  PubMed  CAS  Google Scholar 

  • Millan MJ, Brocco M, Gobert A, Schreiber R, Dekeyne A (1999) S-16924 [(R)-2-[1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yloxy)-ethyl]- pyrrolidin-3yl]-1-(4-fluorophenyl)-ethanone], a novel, potential antipsychotic with marked serotonin1A agonist properties: III. Anxiolytic actions in comparison with clozapine and haloperidol. J Pharmacol Exp Ther 288:1002–1014

    PubMed  CAS  Google Scholar 

  • Moghaddam B, Adams BW (1998) Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 281:1349–1352

    Article  PubMed  CAS  Google Scholar 

  • Moghaddam B, Adams B, Verma A, Daly D (1997) Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci 17:2921–2927

    PubMed  CAS  Google Scholar 

  • Monn JA, Valli MJ, Massey SM, Hansen MM, Kress TJ, Wepsiec JP, Harkness AR, Grutsch JL, Wright RA, Johnson BG, Andis SL, Kingston A, Tomlinson R, Lewis R, Griffey KR, Tizzano JP, Schoepp DD (1999) Synthesis, pharmacological characterization, and molecular modeling of heterobicyclic amino acids related to (+)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylic acid (LY354740): identification of two new potent, selective, and systemically active agonists for group II metabotropic glutamate receptors. J Med Chem 42:1027–1040

    Article  PubMed  CAS  Google Scholar 

  • Olney JW, Farber NB (1995) Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 52:998–1007

    PubMed  CAS  Google Scholar 

  • Ossowska K, Pietraszek M, Wardas J, Nowak G, Zajaczkowski W, Wolfarth S, Pilc A (2000) The role of glutamate receptors in antipsychotic drug action. Amino Acids 19:87–94

    Article  PubMed  CAS  Google Scholar 

  • Pinkerton AB, Vernier JM, Schaffhauser H, Rowe BA, Campbell UC, Rodriguez DE, Lorrain DS, Baccei CS, Daggett LP, Bristow LJ (2004) Phenyl-tetrazolyl acetophenones: discovery of positive allosteric potentiatiors for the metabotropic glutamate 2 receptor. J Med Chem 47:4595–4599

    Article  PubMed  CAS  Google Scholar 

  • Rueter LE, Ballard ME, Gallagher KB, Basso AM, Curzon P, Kohlhaas KL (2004) Chronic low dose risperidone and clozapine alleviate positive but not negative symptoms in the rat neonatal ventral hippocampal lesion model of schizophrenia. Psychopharmacology (Berl) 176:312–319

    Article  CAS  Google Scholar 

  • Sams-Dodd F (1998) A test of the predictive validity of animal models of schizophrenia based on phencyclidine and D-amphetamine. Neuropsychopharmacology 18:293–304

    Article  PubMed  CAS  Google Scholar 

  • Schaffhauser H, Rowe BA, Morales S, Chavez-Noriega LE, Yin R, Jachec C, Rao SP, Bain G, Pinkerton AB, Vernier JM, Bristow LJ, Varney MA, Daggett LP (2003) Pharmacological characterization and identification of amino acids involved in the positive modulation of metabotropic glutamate receptor subtype 2. Mol Pharmacol 64:798–810

    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 

  • Schreiber R, Lowe D, Voerste A, De Vry J (2000) LY354740 affects startle responding but not sensorimotor gating or discriminative effects of phencyclidine. Eur J Pharmacol 388:R3–R4

    Article  PubMed  CAS  Google Scholar 

  • Terranova JP, Chabot C, Barnouin MC, Perrault G, Depoortere R, Griebel G, Scatton B (2005) SSR181507, a dopamine D(2) receptor antagonist and 5-HT(1A) receptor agonist, alleviates disturbances of novelty discrimination in a social context in rats, a putative model of selective attention deficit. Psychopharmacology (Berl) 181:134–144

    Article  CAS  Google Scholar 

  • Wang C, McInnis J, Ross-Sanchez M, Shinnick-Gallagher P, Wiley JL, Johnson KM (2001) Long-term behavioral and neurodegenerative effects of perinatal phencyclidine administration: implications for schizophrenia. Neuroscience 107:535–550

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors wish to thank Annette Janik and Regina Eichhoff for expert technical assistance.

Author information

Authors and Affiliations

  1. Neuroscience Discovery Research, Abbott, 67061, Ludwigshafen, Germany

    Silke Harich, Gerhard Gross & Anton Bespalov

  2. Evotec Neurosciences GmbH, Centrum für innovative Medizin, Falkenried 88, 20251, Hamburg, Germany

    Silke Harich

Authors
  1. Silke Harich
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gerhard Gross
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anton Bespalov
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Silke Harich.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Harich, S., Gross, G. & Bespalov, A. Stimulation of the metabotropic glutamate 2/3 receptor attenuates social novelty discrimination deficits induced by neonatal phencyclidine treatment. Psychopharmacology 192, 511–519 (2007). https://doi.org/10.1007/s00213-007-0742-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-007-0742-y

Keywords

Search

Navigation