title: Combined administration of an mGlu2/3 receptor agonist and a 5-HT 2A receptor antagonist markedly attenuate the psychomotor-activating and neurochemical effects of psychostimulants.
abstract: BACKGROUND
  It was recently reported that administration of the metabotropic glutamate 2 and 3 (mGlu2/3) receptor agonist prodrug LY2140023 to schizophrenic patients decreased positive symptoms. However, at the single, potentially suboptimal, dose that was tested, LY2140023 trended towards being inferior to olanzapine on several indices of efficacy within the Positive and Negative Syndrome Scale.
  
  
  OBJECTIVE
  In this study, we examined whether the antipsychotic potential of mGlu2/3 receptor agonism can be enhanced with 5-HT(2A) receptor antagonism.
  
  
  METHODS
  Specifically, we characterized the effects of co-administering submaximally effective doses of the 5-HT(2A) receptor antagonist M100907 (0.2 mg/kg) and the mGlu2/3 receptor agonist LY379268 (1 mg/kg) on amphetamine-induced and MK-801-induced psychomotor activity in rats, an assay sensitive to antipsychotics. We also determined the effects of co-administering these two compounds on MK-801-induced dopamine and norepinephrine efflux in the nucleus accumbens (NAc).
  
  
  RESULTS
  At the submaximally effective doses tested, the effects of M100907 and LY379268 on amphetamine-induced and MK-801-induced psychomotor activity were significantly greater when given together than when given separately. Furthermore, coadministration of these doses of M100907 and LY379268 reduced MK-801-induced dopamine efflux in the NAc. This effect on dopamine release was not observed with the administration of either compound alone, even at higher doses that attenuated MK-801-induced psychomotor activity.
  
  
  CONCLUSIONS
  Our results suggest that a single compound having both mGlu2/3 receptor agonist and 5-HT(2A) receptor antagonist activity, or coadministration of two compounds selective for these receptors, could be superior in terms of efficacy and/or reduced side-effect liability relative to an mGlu2/3 receptor agonist alone.
authors.affiliation: Department of Schizophrenia Research, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA. jason_uslaner@merck.com
authors.forename: Jason M
authors.initials: JM
authors.lastname: Uslaner
authors.forename: Sean M
authors.initials: SM
authors.lastname: Smith
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Huszar
authors.forename: Rashida
authors.initials: R
authors.lastname: Pachmerhiwala
authors.forename: Richard M
authors.initials: RM
authors.lastname: Hinchliffe
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Vardigan
authors.forename: Pete H
authors.initials: PH
authors.lastname: Hutson
mesh_terms: D000596:Amino Acids / Q000494:pharmacology*; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005464:Fluorobenzenes / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology*
chemical_list: D000596:Amino Acids; D014150:Antipsychotic Agents; D018690:Excitatory Amino Acid Agonists; D005464:Fluorobenzenes; C534551:LY 2140023; D010880:Piperidines; D018094:Receptors, Metabotropic Glutamate; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D016291:Dizocilpine Maleate; D000661:Amphetamine; C079049:volinanserin; D004298:Dopamine; D009638:Norepinephrine
references.citation: J Neural Transm Gen Sect. 1992;89(1-2):1-10
references.pmid: 1358122
references.citation: Psychopharmacology (Berl). 2001 Mar 1;154(2):189-97
references.pmid: 11314681
references.citation: Neuropsychopharmacology. 2005 Jul;30(7):1324-33
references.pmid: 15688082
references.citation: J Pharm Pharmacol. 1972 May;24(5):408-9
references.pmid: 4403814
references.citation: Eur J Pharmacol. 2000 Jul 21;400(2-3):221-4
references.pmid: 10988337
references.citation: J Pharmacol Exp Ther. 2007 Aug;322(2):862-70
references.pmid: 17519387
references.citation: Arch Int Pharmacodyn Ther. 1969 Mar;178(1):166-76
references.pmid: 5353469
references.citation: J Med Chem. 1999 Mar 25;42(6):1027-40
references.pmid: 10090786
references.citation: J Pharmacol Exp Ther. 1966 Mar;151(3):339-52
references.pmid: 5938473
references.citation: J Pharm Pharmacol. 1972 May;24(5):412-4
references.pmid: 4403816
references.citation: Biol Psychiatry. 1998 Sep 15;44(6):508-15
references.pmid: 9777184
references.citation: J Pharmacol Exp Ther. 2001 Oct;299(1):12-20
references.pmid: 11561058
references.citation: Ann N Y Acad Sci. 2003 Nov;1003:309-17
references.pmid: 14684454
references.citation: Psychopharmacology (Berl). 1988;96(3):395-9
references.pmid: 3146774
references.citation: Biol Psychiatry. 2001 Nov 15;50(10):750-7
references.pmid: 11720693
references.citation: Pharmacol Biochem Behav. 2001 Mar;68(3):363-70
references.pmid: 11325387
references.citation: Eur J Pharmacol. 1994 Jan 14;251(2-3):229-36
references.pmid: 8149978
references.citation: Jpn J Pharmacol. 2001 Dec;87(4):277-87
references.pmid: 11829147
references.citation: Behav Brain Res. 2002 Nov 15;136(2):339-48
references.pmid: 12429395
references.citation: Nat Med. 2007 Sep;13(9):1102-7
references.pmid: 17767166
references.citation: Psychopharmacology (Berl). 1988;96(4):521-7
references.pmid: 2907662
references.citation: Brain Res. 2000 Jan 3;852(1):198-207
references.pmid: 10661513
references.citation: J Pharmacol Exp Ther. 1996 Jun;277(3):1541-9
references.pmid: 8667221
references.citation: J Pharmacol Exp Ther. 1989 Oct;251(1):238-46
references.pmid: 2571717
references.citation: Neuropsychopharmacology. 2000 Nov;23(5):569-76
references.pmid: 11027922
references.citation: Naunyn Schmiedebergs Arch Pharmacol. 2000 Jan;361(1):39-46
references.pmid: 10651145
references.citation: J Pharmacol Exp Ther. 2000 Jan;292(1):76-87
references.pmid: 10604933
references.citation: Psychopharmacology (Berl). 2004 Dec;177(1-2):23-34
references.pmid: 15167980
references.citation: Nature. 2008 Mar 6;452(7183):93-7
references.pmid: 18297054
references.citation: Brain Res. 2001 Mar 16;894(2):167-80
references.pmid: 11251190
references.citation: Science. 1998 Aug 28;281(5381):1349-52
references.pmid: 9721099
references.citation: Psychopharmacology (Berl). 2000 Mar;148(4):423-9
references.pmid: 10928316
references.citation: Neuropsychopharmacology. 2003 Sep;28(9):1622-32
references.pmid: 12825094
references.citation: Am J Psychiatry. 2004 Jun;161(6):975-84
references.pmid: 15169685
references.citation: Nat Med. 2007 Sep;13(9):1018-9
references.pmid: 17828217
references.citation: Psychopharmacology (Berl). 2002 Aug;163(1):54-61
references.pmid: 12185400
references.citation: Psychopharmacol Bull. 1989;25(3):390-2
references.pmid: 2576319
references.citation: J Pharmacol Exp Ther. 2002 Dec;303(3):919-27
references.pmid: 12438510
references.citation: J Clin Psychopharmacol. 1995 Feb;15(1 Suppl 1):11S-18S
references.pmid: 7730496
references.citation: Life Sci. 1965 May;4(10):1037-48
references.pmid: 5838507
references.citation: Eur Neuropsychopharmacol. 1996 Mar;6(1):29-38
references.pmid: 8866935
references.citation: Psychopharmacologia. 1974 Mar 21;36(1):1-16
references.pmid: 4151923
references.citation: J Neural Transm. 1989;75(3):221-6
references.pmid: 2538557
references.citation: Pharmacol Biochem Behav. 2002 Sep;73(2):333-7
references.pmid: 12117587
references.citation: Eur J Pharmacol. 1995 Sep 5;283(1-3):55-62
references.pmid: 7498321
references.citation: J Pharmacol Exp Ther. 2005 Dec;315(3):1181-7
references.pmid: 16123306
references.citation: Behav Brain Res. 2002 Aug 21;134(1-2):467-77
references.pmid: 12191833