EFFECTS OF LINOPIRDINE (DUP-996) AND X9121 ON AGE-RELATED MEMORY IMPAIRMENTS AND ON THE CHOLINERGIC SYSTEM

Linopirdine (DuP 996) has been shown to enhance K+-stimulated release of acetylcholine from cerebral cortex, striatum, and hippocampus of ra ts in vitro. X9121 is a structurally different compound identified as having similar release properties. The present experiments compare the effects of linopirdine and X9121 on cognitive deficits in aged rats, and on the pharmacological properties in young rats. For cognitive tes ting, aged male Fischer-344 rats (24 months old, n = 116) received eit her vehicle or one of 5 doses of linopirdine or X9121 prior to behavio ral testing; young rats (4 months old, n = 13) were controls and recei ved vehicle prior to testing. Place discrimination and repeated acquis ition were tested in the water maze, and a variety of sensorimotor tas ks were given. Aging impaired performance in all tasks. Linopirdine (0 .25, 2.5, and 8.5 mg/kg po [0.64, 7.4, and 25 mu mol/kg]) and X9121 (0 .85 and 8.5 mg/kg po [2.1 and 24 mu mol/kg]) moderately improved place discrimination. None of the doses tested improved repeated acquisitio n or sensorimotor function. No behavioral indications of toxicity were observed. Acetylcholine release, acetylcholinesterase (AChE) inhibiti on, and nicotinic and muscarinic binding were measured in vitro in cer ebral cortical tissue from young male Wistar rats (2 months old). Both linopirdine and X9121 enhanced K+-stimulated release from cerebral co rtex; X9121 produced greater release with a broader range of active co ncentrations. Linopirdine weakly inhibited AChE (1,000 x weaker than p hysostigmine) and X9121 did not. Neither drug bound significantly to m uscarinic or nicotinic cholinergic receptors. These results support th e hypothesis that linopirdine and X9121 have some cognition enhancing properties which may be due to enhancement of stimulation-induced acet ylcholine release. These results suggest that linopirdine and X9121 ma y be useful in treating disorders involving cognitive impairment. (C) 1994 Wiley-Liss, Inc.