Psychopharmacology

, Volume 193, Issue 1, pp 121–136 | Cite as

In vivo pharmacological characterization of the structurally novel, potent, selective mGlu2/3 receptor agonist LY404039 in animal models of psychiatric disorders

  • Linda M. Rorick-Kehn
  • Bryan G. Johnson
  • Karen M. Knitowski
  • Craig R. Salhoff
  • Jeffrey M. Witkin
  • Kenneth W. Perry
  • Kelly I. Griffey
  • Joseph P. Tizzano
  • James A. Monn
  • David L. McKinzie
  • Darryle D. Schoepp
Original Investigation

Abstract

Rationale

Data from both preclinical and clinical studies have provided proof of concept that modulation of limbic and forebrain glutamate, via mGlu2/3 receptor agonists, might provide therapeutic benefits in many psychiatric disorders including schizophrenia and anxiety.

Objective

The aim of this study was to assess the efficacy of a structurally novel, potent, selective mGlu2/3 receptor agonist with improved bioavailability (LY404039) in animal models predictive of antipsychotic and anxiolytic efficacy.

Materials and methods

LY404039 was assessed in amphetamine- and phencyclidine-induced hyperlocomotion, conditioned avoidance responding, fear-potentiated startle, marble burying, and rotarod behavioral tests. Monoamine release and turnover were assessed using microdialysis and ex vivo tissue levels.

Results

LY404039 attenuated amphetamine- and phencyclidine-induced hyperlocomotion (3–30 and 10 mg/kg, respectively). LY404039 (3–10 mg/kg) inhibited conditioned avoidance responding. LY404039 also reduced fear-potentiated startle in rats (3–30 μg/kg) and marble burying in mice (3–10 mg/kg), indicating anxiolytic-like effects. Importantly, LY404039 did not produce sedative effects or motor impairment as measured by rotarod performance and lack of escape failures in the conditioned avoidance task (at doses up to 30 and 10 mg/kg, respectively). LY404039 (10 mg/kg) also increased dopamine and serotonin release/turnover in the prefrontal cortex.

Conclusions

These results demonstrate the broad preclinical efficacy of LY404039 across multiple animal models of antipsychotic and anxiolytic efficacy. Additionally, this compound modulates mesocortical neurotransmission and provides a novel mechanism for the treatment of psychiatric disorders that may be associated with improved efficacy and reduced incidence of undesirable side effects. As glutamatergic dysfunction has been linked to the etiology of schizophrenia, clinical studies with more potent mGlu2/3 agonists, such as LY404039, may be useful to explore the validity of this hypothesis.

Keywords

Metabotropic glutamate (mGlu) receptors mGlu2/3 receptor agonist Anxiety Schizophrenia Psychiatric disorders Animal models Anxiolytic Antipsychotic 

References

  1. Ascher-Svanum H, Stensland MD, Kinon BJ, Tollefson GD (2005) Weight gain as a prognostic indicator of therapeutic improvement during acute treatment of schizophrenia with placebo or active antipsychotic. J Psychopharmacol 19:110–117PubMedCrossRefGoogle Scholar
  2. Bergink V, Westenberg HG (2005) Metabotropic glutamate II receptor agonists in panic disorder: a double blind clinical trial with LY354740. Int Clin Psychopharmacol 20:291–293PubMedCrossRefGoogle Scholar
  3. Bergink V, van Megen HJ, Westenberg HG (2004) Glutamate and anxiety. Eur Neuropsychopharmacol 14:175–183PubMedCrossRefGoogle Scholar
  4. Bueno AB, Collado I, de Dios A, Dominguez C, Martin JA, Martin LM, Martinez-Grau MA, Montero C, Pedregal C, Catlow J, Coffey DS, Clay MP, Dantzig AH, Lindstrom T, Monn JA, Jiang H, Schoepp DD, Stratford RE, Tabas LB, Tizzano JP, Wright RA, Herin MF (2005) Dipeptides as effective prodrugs of the unnatural amino acid (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY354740), a selective group II metabotropic glutamate receptor agonist. J Med Chem 48:5305–5320PubMedCrossRefGoogle Scholar
  5. 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 291:161–170PubMedGoogle Scholar
  6. Cartmell J, Schoepp DD (2000) Regulation of neurotransmitter release by metabotropic glutamate receptors. J Neurochem 75:889–907PubMedCrossRefGoogle Scholar
  7. Cartmell J, Perry KW, Salhoff CR, Monn JA, Schoepp DD (2000a) The potent, selective mGlu2/3 receptor agonist LY379268 increases extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindole-3-acetic acid in the medial prefrontal cortex of the freely moving rat. J Neurochem 75:1147–1154PubMedCrossRefGoogle Scholar
  8. Cartmell J, Salhoff CR, Perry KW, Monn JA, Schoepp DD (2000b) Dopamine and 5-HT turnover are increased by the mGlu2/3 receptor agonist LY379268 in rat medial prefrontal cortex, nucleus accumbens and striatum. Brain Res 887:378–384PubMedCrossRefGoogle Scholar
  9. Galici R, Echemendia NG, Rodriguez AL, Conn PJ (2005) A selective allosteric potentiator of metabotropic glutamate (mGlu) 2 receptors has effects similar to an orthosteric mGlu2/3 receptor agonist in mouse models predictive of antipsychotic activity. J Pharmacol Exp Ther 315:1181–1187PubMedCrossRefGoogle Scholar
  10. Goldman-Rakic PS (1999) The relevance of the dopamine-D1 receptor in the cognitive symptoms of schizophrenia. Neuropsychopharmacology 21:S170–S180CrossRefGoogle Scholar
  11. Grillon C, Cordova J, Levine LR, Morgan CA 3rd (2003) Anxiolytic effects of a novel group II metabotropic glutamate receptor agonist (LY354740) in the fear-potentiated startle paradigm in humans. Psychopharmacology (Berl) 168:446–454CrossRefGoogle Scholar
  12. Gudex C (1991) Adverse effects of benzodiazepines. Soc Sci Med 33:587–596PubMedCrossRefGoogle Scholar
  13. Helton DR, Tizzano JP, Monn JA, Schoepp DD, Kallman MJ (1997) LY354740: a metabotropic glutamate receptor agonist which ameliorates symptoms of nicotine withdrawal in rats. Neuropharmacology 36:1511–1516PubMedCrossRefGoogle Scholar
  14. 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 284:651–660PubMedGoogle Scholar
  15. Heresco-Levy U (2005) Glutamatergic neurotransmission modulators as emerging new drugs for schizophrenia. Expert Opin Emerg Drugs 10:827–844PubMedCrossRefGoogle Scholar
  16. Iijima M, Shimazaki T, Ito A, Chaki S (2007) Effects of metabotropic glutamate 2/3 receptor antagonists in the stress-induced hyperthermia test in singly housed mice. Psychopharmacology (Berl) 190:233–239CrossRefGoogle Scholar
  17. Johnson JT, Mattiuz EL, Chay SH, Herman JL, Wheeler WJ, Kassahun K, Swanson SP, Phillips DL (2002) The disposition, metabolism, and pharmacokinetics of a selective metabotropic glutamate receptor agonist in rats and dogs. Drug Metab Dispos 30:27–33PubMedCrossRefGoogle Scholar
  18. 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) 179:271–283CrossRefGoogle Scholar
  19. Kellner M, Muhtz C, Stark K, Yassouridis A, Arlt J, Wiedemann K (2005) Effects of a metabotropic glutamate(2/3) receptor agonist (LY544344/LY354740) on panic anxiety induced by cholecystokinin tetrapeptide in healthy humans: preliminary results. Psychopharmacology (Berl) 179:310–315CrossRefGoogle Scholar
  20. Kingston AE, Ornstein PL, Wright RA, Johnson BG, Mayne NG, Burnett JP, Belagaje R, Wu S, Schoepp DD (1998) LY341495 is a nanomolar potent and selective antagonist of group II metabotropic glutamate receptors. Neuropharmacology 37:1–12PubMedCrossRefGoogle Scholar
  21. Krystal JH, Abi-Saab W, Perry E, D’Souza DC, Liu N, Gueorguieva R, McDougall L, Hunsberger T, Belger A, Levine L, Breier A (2005a) Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects. Psychopharmacology (Berl) 179:303–309CrossRefGoogle Scholar
  22. Krystal JH, Perry Jr EB, Gueorguieva R, Belger A, Madonick SH, Abi-Dargham A, Cooper TB, Macdougall L, Abi-Saab W, D’Souza DC (2005b) Comparative and interactive human psychopharmacologic effects of ketamine and amphetamine: implications for glutamatergic and dopaminergic model psychoses and cognitive function. Arch Gen Psychiatry 62:985–994PubMedCrossRefGoogle Scholar
  23. Li XM, Perry KW, Wong DT, Bymaster FP (1998) Olanzapine increases in vivo dopamine and norepinephrine release in rat prefrontal cortex, nucleus accumbens and striatum. Psychopharmacology (Berl) 136:153–161CrossRefGoogle Scholar
  24. 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 29:502–513PubMedCrossRefGoogle Scholar
  25. Linden AM, Bergeron M, Schoepp DD (2005a) Comparison of c-Fos induction in the brain by the mGlu2/3 receptor antagonist LY341495 and agonist LY354740: evidence for widespread endogenous tone at brain mGlu2/3 receptors in vivo. Neuropharmacology 49(Suppl 1):120–134PubMedCrossRefGoogle Scholar
  26. Linden AM, Shannon H, Baez M, Yu JL, Koester A, Schoepp DD (2005b) Anxiolytic-like activity of the mGLU2/3 receptor agonist LY354740 in the elevated plus maze test is disrupted in metabotropic glutamate receptor 2 and 3 knock-out mice. Psychopharmacology (Berl) 179:284–291CrossRefGoogle Scholar
  27. Marek GJ, Wright RA, Schoepp DD, Monn JA, Aghajanian GK (2000) Physiological antagonism between 5-hydroxytryptamine(2A) and group II metabotropic glutamate receptors in prefrontal cortex. J Pharmacol Exp Ther 292:76–87PubMedGoogle Scholar
  28. Moghaddam B (2002) Stress activation of glutamate neurotransmission in the prefrontal cortex: implications for dopamine-associated psychiatric disorders. Biol Psychiatry 51:775–787PubMedCrossRefGoogle Scholar
  29. Moghaddam B, Adams BW (1998) Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 281:1349–1352PubMedCrossRefGoogle Scholar
  30. 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 40:528–537PubMedCrossRefGoogle Scholar
  31. Monn JA, Massey SM, Valli MJ, Henry SS, Stephenson GA, Bures M, Herin M, Catlow J, Giera D, Wright RA, Johnson BG, Andis SL, Kingston A, Schoepp DD (2007) Synthesis and metabotropic glutamate receptor activity of S-oxidized variants of (−)-4-amino-2-thiabicyclo-[3.1.0]hexane-4,6-dicarboxylate: identification of potent, selective, and orally bioavailable agonists for mGlu2/3 receptors. J Med Chem 50:233–240PubMedCrossRefGoogle Scholar
  32. Morris BJ, Cochran SM, Pratt JA (2005) PCP: from pharmacology to modelling schizophrenia. Curr Opin Pharmacol 5:101–106PubMedCrossRefGoogle Scholar
  33. Nakazato A, Sakagami K, Yasuhara A, Ohta H, Yoshikawa R, Itoh M, Nakamura M, Chaki S (2004) Synthesis, in vitro pharmacology, structure-activity relationships, and pharmacokinetics of 3-alkoxy-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent and selective group II metabotropic glutamate receptor antagonists. J Med Chem 47:4570–4587PubMedCrossRefGoogle Scholar
  34. Ohishi H, Shigemoto R, Nakanishi S, Mizuno N (1993a) Distribution of the messenger RNA for a metabotropic glutamate receptor, mGluR2, in the central nervous system of the rat. Neuroscience 53:1009–1018PubMedCrossRefGoogle Scholar
  35. Ohishi H, Shigemoto R, Nakanishi S, Mizuno N (1993b) Distribution of the mRNA for a metabotropic glutamate receptor (mGluR3) in the rat brain: an in situ hybridization study. J Comp Neurol 335:252–266PubMedCrossRefGoogle Scholar
  36. Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic, New YorkGoogle Scholar
  37. Rickels K, Rynn M (2002) Pharmacotherapy of generalized anxiety disorder. J Clin Psychiatry 63(Suppl 14):9–16PubMedGoogle Scholar
  38. Rodd ZA, McKinzie DL, Bell RL, McQueen VK, Murphy JM, Schoepp DD, McBride WJ (2006) The metabotropic glutamate 2/3 receptor agonist LY404039 reduces alcohol-seeking but not alcohol self-administration in alcohol-preferring (P) rats. Behav Brain Res 171:207–215CrossRefGoogle Scholar
  39. Rorick-Kehn LM, Perkins EJ, Knitowski KM, Hart JC, Johnson BG, Schoepp DD, McKinzie DL (2006) Improved bioavailability of the mGlu2/3 receptor agonist LY354740 using a prodrug strategy: in vivo pharmacology of LY544344. J Pharmacol Exp Ther 316:905–913PubMedCrossRefGoogle Scholar
  40. Rorick-Kehn LM, Johnson BG, Burkey JL, Wright RA, Calligaro DO, Marek GJ, Nisenbaum ES, Catlow JT, Kingston AE, Giera DD, Herin MF, Monn JA, McKinzie DL, Schoepp DD (2007) Pharmacological and pharmacokinetic properties of a structurally-novel, potent, selective mGlu2/3 receptor agonist: in vitro characterization of LY404039. J Pharmacol Exp Ther (in press) DOI  10.1124/jpet.106.110809
  41. Sachdev PS (2005) Neuroleptic-induced movement disorders: an overview. Psychiatr Clin North Am 28:255–274PubMedCrossRefGoogle Scholar
  42. Sams-Dodd F (1998) Effects of diazepam, citalopram, methadone and naloxone on PCP-induced stereotyped behaviour and social isolation in the rat social interaction test. Neurosci Biobehav Rev 23:287–293PubMedCrossRefGoogle Scholar
  43. Schoepp DD (2001) Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system. J Pharmacol Exp Ther 299:12–20PubMedGoogle Scholar
  44. Schoepp DD, Marek GJ (2002) Preclinical pharmacology of mGlu2/3 receptor agonists: novel agents for schizophrenia? Curr Drug Targets CNS Neurol Disord 1:215–225CrossRefGoogle Scholar
  45. 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 6:189–197PubMedCrossRefGoogle Scholar
  46. 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–R4PubMedCrossRefGoogle Scholar
  47. 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 39:1139–1146PubMedCrossRefGoogle Scholar
  48. Spooren WP, Gasparini F, van der Putten H, Koller M, Nakanishi S, Kuhn R (2000) Lack of effect of LY314582 (a group 2 metabotropic glutamate receptor agonist) on phencyclidine-induced locomotor activity in metabotropic glutamate receptor 2 knockout mice. Eur J Pharmacol 397:R1–R2PubMedCrossRefGoogle Scholar
  49. Spooren WP, 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 435:161–170PubMedCrossRefGoogle Scholar
  50. Steinpreis RE, Anders KA, Branda EM, Kruschel CK (1999) The effects of atypical antipsychotics and phencyclidine (PCP) on rotorod performance. Pharmacol Biochem Behav 63:387–394PubMedCrossRefGoogle Scholar
  51. Swanson CJ, Bures M, Johnson MP, Linden AM, Monn JA, Schoepp DD (2005) Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Nat Rev Drug Discov 4:131–144PubMedCrossRefGoogle Scholar
  52. Takamori K, Hirota S, Chaki S, Tanaka M (2003) Antipsychotic action of selective group II metabotropic glutamate receptor agonist MGS0008 and MGS0028 on conditioned avoidance responses in the rat. Life Sci 73:1721–1728PubMedCrossRefGoogle Scholar
  53. Vandergriff J, Rasmussen K (1999) The selective mGlu2/3 receptor agonist LY354740 attenuates morphine-withdrawal-induced activation of locus coeruleus neurons and behavioral signs of morphine withdrawal. Neuropharmacology 38:217–222PubMedCrossRefGoogle Scholar
  54. Wadenberg ML, Soliman A, VanderSpek SC, Kapur S (2001) Dopamine D(2) receptor occupancy is a common mechanism underlying animal models of antipsychotics and their clinical effects. Neuropsychopharmacology 25:633–641PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Linda M. Rorick-Kehn
    • 1
  • Bryan G. Johnson
    • 1
  • Karen M. Knitowski
    • 1
  • Craig R. Salhoff
    • 1
  • Jeffrey M. Witkin
    • 1
  • Kenneth W. Perry
    • 1
  • Kelly I. Griffey
    • 1
  • Joseph P. Tizzano
    • 2
  • James A. Monn
    • 1
  • David L. McKinzie
    • 1
  • Darryle D. Schoepp
    • 1
  1. 1.Neuroscience Discovery Research, Lilly Research LaboratoriesEli Lilly and CompanyIndianapolisUSA
  2. 2.DOV Pharmaceuticals, Continental PlazaHackensackUSA

Personalised recommendations