title: Dose-dependent effect of CDPPB, the mGluR5 positive allosteric modulator, on recognition memory is associated with GluR1 and CREB phosphorylation in the prefrontal cortex and hippocampus.
abstract: In the search for strategies to treat schizophrenia, attention has focused on enhancing NMDA receptor function. In vitro experiments show that metabotropic glutamate 5 receptor (mGluR5) activation enhances NMDA receptor activity, and in vivo experiments indicate that mGluR5 positive allosteric modulators (PAMs) are effective in preclinical assays measuring antipsychotic potential and cognition. Here we characterized the dose-effect function of CDPPB (3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide), an mGluR5 PAM, on novel object recognition memory in unimpaired Wistar Hannover rats (0, 10 or 30 mg/kg CDPPB) and animals with an MK-801-induced deficit (0, 3, 10, or 30 mg/kg CDPPB). In each experiment compound was given 30 min prior to the first exposure in order to affect acquisition/consolidation of the memory. In both cases, an inverted-U-shaped dose-effect function was observed, with lower doses improving recognition but higher doses having no effect. We then examined the effects of CDPPB (0, 3, 10, or 30 mg/kg) on markers of synaptic plasticity in prefrontal cortex and hippocampus, focusing on the expression and phosphorylation status of proteins involved in NMDA related signaling, including the NMDA receptor subunits NR1 and NR2B, the AMPA receptor subunit GluR1, alphaCa((2+))/CaM dependent Ser-Thr kinases II (alphaCaMKII), and the transcription factor CREB. Expression and phosphorylation of many of these proteins, particularly in the prefrontal cortex, were also characterized by an inverted-U-shaped dose-effect function. Taken together, these findings show that mGluR5 activation enhances NMDA receptor function and markers of neuronal plasticity commensurate with improvements in recognition memory. However, the effects of CDPPB are heavily dependent on dose, with higher doses being ineffective in improving recognition memory and producing downstream effects consistent with heightened NMDA receptor activation. These findings may have important implications for the development of mGluR5 PAMs to treat schizophrenia.
authors.affiliation: Department of Schizophrenia Research, Merck & Co., Inc., West Point, PA 19486, USA. jason_uslaner@merck.com
authors.forename: Jason M
authors.initials: JM
authors.lastname: Uslaner
authors.forename: Sophie
authors.initials: S
authors.lastname: Parmentier-Batteur
authors.forename: Rosemarie B
authors.initials: RB
authors.lastname: Flick
authors.forename: Nathaniel O
authors.initials: NO
authors.lastname: Surles
authors.forename: June S H
authors.initials: JS
authors.lastname: Lam
authors.forename: Caitlyn H
authors.initials: CH
authors.lastname: McNaughton
authors.forename: Marlene A
authors.initials: MA
authors.lastname: Jacobson
authors.forename: Pete H
authors.initials: PH
authors.lastname: Hutson
mesh_terms: D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002491:Central Nervous System Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D016291:Dizocilpine Maleate; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects* / Q000502:physiology
chemical_list: D001549:Benzamides; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002491:Central Nervous System Agents; D017362:Cyclic AMP Response Element-Binding Protein; D016291:Dizocilpine Maleate; D011720:Pyrazoles; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C494553:3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide; C409466:NR1 NMDA receptor; C121001:NR2B NMDA receptor