The 5-HT1A antagonist, WAY 100 635, alleviates cognitive impairments induced by dizocilpine (MK-801) in monkeys

Central glutamate neurotransmission is modulated by an upregulatory choline rgic influence and an inhibitory serotonergic influence. In Alzheimer's dis ease, cognitive decline is associated with loss of both glutamatergic and c holinergic neurones (Francis et al., 1992, Progress in Neurobiology 39, 517 -545). While therapeutic strategies for alleviating this cognitive decline have concentrated on restoring cholinergic tone, we suggest that 5-HT1A ant agonists also have the potential to alleviate the cognitive symptoms of Alz heimer's disease. Previous studies have shown that dizocilpine. (MK-801), a glutamatergic antagonist acting at the NMDA receptor, produces learning im pairments in the common marmoset, a non-human primate. Specifically, it imp airs the acquisition of shape discrimination and visuospatial conditional t asks, at doses that do not affect locomotor behaviour or coordination (Hard er et al., 1998, Society for Neuroscience Abstracts 23(1), 219). In the pre sent study we investigated the effects of WAY 100 635, a 5-HT1A antagonist, on the cognitive deficits induced by dizocilpine. The number of trials req uired to learn each type of task under combined treatment with dizocilpine and WAY 100 635 was significantly lower than under dizocilpine treatment al one, and did not differ significantly from the number of trials required un der saline, demonstrating that the cognitive effects of glutamatergic block ade can be overcome by treatment with a 5-HT1A antagonist. (C) 2000 Elsevie r Science Ltd. All rights reserved.