title: MK-801 produces a deficit in sucrose preference that is reversed by clozapine, D-serine, and the metabotropic glutamate 5 receptor positive allosteric modulator CDPPB: relevance to negative symptoms associated with schizophrenia?
abstract: Currently prescribed antipsychotics attenuate the positive symptoms of schizophrenia but fail or only mildly improve negative symptoms. The present study aimed to establish an animal model of negative symptoms by examining the effects of the NMDA receptor antagonist MK-801 on sucrose preference. We sought to validate the model by examining the effects of clozapine and D-serine, for which there are positive clinical data regarding their effects on negative symptoms, and haloperidol which is clinically ineffective. We extended our analysis by examining CDPPB, an mGlu5 receptor positive allosteric modulator. Acute MK-801 produced effects indicative of a shift in the hedonic experience of sucrose not confounded by disruptions in motor abilities or taste as revealed by: 1) a decrease in sucrose intake at low concentrations (0.8% or 1.2%), but no effect on water, 2) an increase in consumption for higher (7%) sucrose concentrations, reflecting a shift to the right in the concentration-consumption curve, and 3) no effect on quinine intake. Sub-chronic clozapine and acute d-serine attenuated the MK-801-induced deficit in 1.2% sucrose consumption, whereas sub-chronic haloperidol (0.02 mg/kg) did not. Finally, acute treatment with CDPPB also attenuated this deficit. These data suggest that this model may be useful for identifying novel agents that improve negative symptoms, and that compounds which enhance NMDA receptor function, such as mGlu5 receptor PAMs, may have clinical utility in this regard.
authors.affiliation: Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Vardigan
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Huszar
authors.forename: Caitlyn H
authors.initials: CH
authors.lastname: McNaughton
authors.forename: Peter H
authors.initials: PH
authors.lastname: Hutson
authors.forename: Jason M
authors.initials: JM
authors.lastname: Uslaner
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008297:Male; D011720:Pyrazoles / Q000494:pharmacology*; D011803:Quinine / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects*; D012559:Schizophrenia / Q000503:physiopathology*; D012694:Serine / Q000494:pharmacology*; D013395:Sucrose / Q000008:administration & dosage*
chemical_list: C494553:3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide; D001549:Benzamides; D018691:Excitatory Amino Acid Antagonists; D011720:Pyrazoles; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D012694:Serine; D013395:Sucrose; D016291:Dizocilpine Maleate; D011803:Quinine; D003024:Clozapine