title: Stimulation of metabotropic glutamate (mGlu) 2 receptor and blockade of mGlu1 receptor improve social memory impairment elicited by MK-801 in rats.
abstract: Glutamatergic dysfunction has been implicated in psychiatric disorders such as schizophrenia. Both the stimulation of the metabotropic glutamate (mGlu) 2/3 receptor and the blockade of the mGlu1 receptor have been shown to be effective in a number of animal models of schizophrenia. However, the efficacy for social cognition, which is poorly managed by current medication, has not been fully addressed. The present study evaluated the effects of an mGlu2/3-receptor agonist and an mGlu1-receptor antagonist on social memory impairment in rats. Pretreatment with an mGlu2/3-receptor agonist, (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268), or an mGlu1-receptor antagonist, (3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone (JNJ16259685), improved social memory impairment induced by 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801) without affecting the social interactions. In addition, the intraperitoneal administration of an mGlu2-receptor potentiator, 3'-[[(2-cyclopentyl-2,3-dihydro-6,7-dimethyl-1-oxo-1H-inden-5-yl)oxy]methyl]-[1,1'-biphenyl]-4-carboxylic acid (BINA), also improved the MK-801-induced impairment of social memory, which was blocked by pretreatment with an mGlu2/3-receptor antagonist, (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495). These findings indicate that both the stimulation of the mGlu2 receptor and the inhibition of an mGlu1 receptor improve social memory impairment elicited by MK-801, and both manipulations could be effective approaches for the treatment of certain cognitive dysfunctions observed in schizophrenic patients.
authors.affiliation: Discovery Pharmacology I, Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., Japan.
authors.forename: Hirohiko
authors.initials: H
authors.lastname: Hikichi
authors.forename: Ayaka
authors.initials: A
authors.lastname: Kaku
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Karasawa
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Chaki
mesh_terms: D000596:Amino Acids / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology / Q000627:therapeutic use; D016291:Dizocilpine Maleate / Q000009:adverse effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000502:physiology; D021641:Recognition, Psychology / Q000187:drug effects; D014966:Xanthenes / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C495417:(3,4-dihydro-2H-pyrano(2,3)b-quinolin-7-yl)-(cis-4-methoxycyclohexyl) methanone; D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018691:Excitatory Amino Acid Antagonists; C114624:LY 341495; C118218:LY 379268; D011804:Quinolines; D018094:Receptors, Metabotropic Glutamate; D014966:Xanthenes; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; C104077:metabotropic glutamate receptor type 1; D016291:Dizocilpine Maleate