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 cholinergic influence and an inhibitory serotonergic influence. In Alzheimer's disease, cognitive decline is associated with loss of both glutamatergic and cholinergic 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 antagonists also have the potential to alleviate the cognitive symptoms of Alzheimer's disease. Previous studies have shown that dizocilpine (MK-801), a glutamatergic antagonist acting at the NMDA receptor, produces learning impairments in the common marmoset, a non-human primate. Specifically, it impairs the acquisition of shape discrimination and visuospatial conditional tasks, at doses that do not affect locomotor behaviour or coordination (Harder et al., 1998, Society for Neuroscience Abstracts 23(1), 219). In the present study we investigated the effects of WAY 100 635, a 5-HT1A antagonist, on the cognitive deficits induced by dizocilpine. The number of trials required to learn each type of task under combined treatment with dizocilpine and WAY 100 635 was significantly lower than under dizocilpine treatment alone, and did not differ significantly from the number of trials required under saline, demonstrating that the cognitive effects of glutamatergic blockade can be overcome by treatment with a 5-HT1A antagonist.