SUBCHRONIC INTRAVENTRICULAR INFUSION OF QUINOLINIC ACID PRODUCES WORKING-MEMORY IMPAIRMENT - A MODEL OF PROGRESSIVE EXCITOTOXICITY

It has been proposed by Yamada et al. [Neurosci. Lett. 118: 128-131 (1 990); J. Pharmacobiodyn. 14: 351-355 (1991)] that subchronic i.c.v. in fusion of the NMDA receptor agonist quinolinic acid may serve as a mod el for some aspects of neurodegenerative dementia. In the present stud y, quinolinic acid (9 mM) was infused i.c.v. by ALZET osmotic minipump s for 2 weeks. This treatment produced a short-term working memory def icit in the T-maze (alternation) but no change in reversal learning in the same test. The working memory deficit in the T-maze was progressi ve i.e. seen after 14, but not 3 days of infusion and persisted for at least for 3 weeks after the termination of the infusion. Histological examination revealed a modest decrease in the number of cells in the nucleus basalis magnocellularis but not in the striatum, entorhinal co rtex, or hippocampus. However, in most of the structures studied, morp hological changes such as swollen somata and irregular shape were obse rved indicative of alterations in neuronal function. Autoradiography i n the hippocampus revealed a decrease in [H-3]hemicholinium and [H-3]q uinuclidinyl benzilate (QNB) binding to choline uptake sites and musca rinic receptors respectively. Surprisingly no change was observed in [ H-3]MK-801 binding to NMDA receptor channels in the hippocampus and co rtex. The subchronic infusion of quinolinic acid may serve as a model of progressive deterioration of cognitive functions. (C) 1996 Elsevier Science Ltd.