title: Source memory in rats is impaired by an NMDA receptor antagonist but not by PSD95-nNOS protein-protein interaction inhibitors.
abstract: Limitations of preclinical models of human memory contribute to the pervasive view that rodent models do not adequately predict therapeutic efficacy in producing cognitive impairments or improvements in humans. We used a source-memory model (i.e., a representation of the origin of information) we developed for use in rats to evaluate possible drug-induced impairments of both spatial memory and higher order memory functions in the same task. Memory impairment represents a major barrier to use of NMDAR antagonists as pharmacotherapies. The scaffolding protein postsynaptic density 95kDa (PSD95) links NMDARs to the neuronal enzyme nitric oxide synthase (nNOS), which catalyzes production of the signaling molecule nitric oxide (NO). Therefore, interrupting PSD95-nNOS protein-protein interactions downstream of NMDARs represents a novel therapeutic strategy to interrupt NMDAR-dependent NO signaling while bypassing unwanted side effects of NMDAR antagonists. We hypothesized that the NMDAR antagonist MK-801 would impair source memory. We also hypothesized that PSD95-nNOS inhibitors (IC87201 and ZL006) would lack the profile of cognitive impairment associated with global NMDAR antagonists. IC87201 and ZL006 suppressed NMDA-stimulated formation of cGMP, a marker of NO production, in cultured hippocampal neurons. MK-801, at doses that did not impair motor function, impaired source memory under conditions in which spatial memory was spared. Thus, source memory was more vulnerable than spatial memory to impairment. By contrast, PSD95-nNOS inhibitors, IC87201 and ZL006, administered at doses that are behaviorally effective in rats, spared source memory, spatial memory, and motor function. Thus, PSD95-nNOS inhibitors are likely to exhibit favorable therapeutic ratios compared to NMDAR antagonists.
authors.affiliation: Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA.
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: Smith
authors.affiliation: Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA; Gill Center for Biomolecular Science, Indiana University, Bloomington, IN, USA.
authors.forename: Zhili
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA; Anagin, LLC, Indianapolis, IN, USA.
authors.forename: Yvonne Y
authors.initials: YY
authors.lastname: Lai
authors.affiliation: Center for Drug Discovery, and Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.
authors.forename: Pushkar M
authors.initials: PM
authors.lastname: Kulkarni
authors.affiliation: Center for Drug Discovery, and Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.
authors.forename: Ganesh A
authors.initials: GA
authors.lastname: Thakur
authors.affiliation: Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA; Gill Center for Biomolecular Science, Indiana University, Bloomington, IN, USA.
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Hohmann
authors.affiliation: Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA. Electronic address: jcrystal@indiana.edu.
authors.forename: Jonathon D
authors.initials: JD
authors.lastname: Crystal
mesh_terms: D000636:Aminosalicylic Acids / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D002478:Cells, Cultured; D002733:Chlorophenols / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D016291:Dizocilpine Maleate / Q000633:toxicity*; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity*; D006624:Hippocampus / Q000166:cytology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism*; D008569:Memory Disorders / Q000139:chemically induced*; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D051381:Rats; D020318:Rats, Long-Evans; D014230:Triazoles / Q000494:pharmacology
chemical_list: C546030:2-((1H-benzo(d)(1,2,3)triazol-5-ylamino)methyl)-4,6-dichlorophenol; D000636:Aminosalicylic Acids; D001596:Benzylamines; D002733:Chlorophenols; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D014230:Triazoles; C000607694:ZL006 compound; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D052248:Nitric Oxide Synthase Type I; D006152:Cyclic GMP
keywords: Episodic memory; MK-801; NMDAR; PSD95-nNOS small molecule inhibitors; Source memory; Spatial memory