H3 receptor antagonism enhances NCAM PSA-mediated plasticity and improves memory consolidation in odor discrimination and delayed match-to-position paradigms.
To further understand the procognitive actions of GSK189254, a histamine H(3) receptor antagonist, we determined its influence on the modulation of hippocampal neural cell adhesion molecule (NCAM) polysialylation (PSA) state, a necessary neuroplastic mechanism for learning and memory consolidation. A 4-day treatment with GSK189254 significantly increased basal expression of dentate polysialylated cells in rats with the maximal effect being observed at 0.03-0.3 mg/kg. At the optimal dose (0.3 mg/kg), GSK189254 enhanced water maze learning and the associated transient increase in NCAM-polysialylated cells. The increase in dentate polysialylated cell frequency induced by GSK189254 was not attributable to enhanced neurogenesis, although it did induce a small, but significant, increase in the survival of these newborn cells. GSK189254 (0.3 mg/kg) was without effect on polysialylated cell frequency in the entorhinal and perirhinal cortex, but significantly increased the diffuse PSA staining observed in the anterior, ventromedial, and dorsomedial aspects of the hypothalamus. Consistent with its ability to enhance the learning-associated, post-training increases in NCAM PSA state, GSK189254 (0.3 mg/kg) reversed the amnesia induced by scopolamine given in the 6-h post-training period after training in an odor discrimination paradigm. Moreover, GSK189254 significantly improved the performance accuracy of a delayed match-to-position paradigm, a task dependent on the prefrontal cortex and degree of cortical arousal, the latter may be related to enhanced NCAM PSA-associated plasticity in the hypothalamus. The procognitive actions of H3 antagonism combined with increased NCAM PSA expression may exert a disease-modifying action in conditions harboring fundamental deficits in NCAM-mediated neuroplasticity, such as schizophrenia and Alzheimer's disease.
Foley
Andrew G
AG
Berand Neuropharmacology, NovaUCD, Belfield Innovation Park, University College Dublin, Dublin, Ireland.
Prendergast
Alison
A
Barry
Claire
C
Scully
Darren
D
Upton
Neil
N
Medhurst
Andrew D
AD
Regan
Ciaran M
CM
D000647:Amnesia / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D000818:Animals; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D002470:Cell Survival / Q000187:drug effects; D004193:Discrimination Learning / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D054828:Histamine H3 Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism*; D055495:Neurogenesis / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009483:Neuropsychological Tests; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D055696:Olfactory Perception / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012601:Scopolamine; D013997:Time Factors
D001552:Benzazepines; D054828:Histamine H3 Antagonists; D019006:Neural Cell Adhesion Molecules; D009536:Niacinamide; C521312:6-((3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy)-N-methyl-3-pyridinecarboxamide; D012601:Scopolamine