5HT antagonists attenuate MK801-impaired radial arm maze performance in rats

Glutamatergic hypofunction occurs in Alzheimer's disease (AD). MK801, a non competitive blocker of glutamate N-methyl-D-aspartate receptors, was used t o disrupt the cognitive performance of rats trained on a delayed nonmatchin g to sample radial maze task. Drugs which act by blocking serotonin (5-HT) receptors were evaluated for their ability to reduce the cognitive impairme nt produced by MK801. Specifically, WAY-100635, a selective 5-HT1A receptor antagonist, buspirone, a 5-HT1A partial agonist, ritanserin, a 5-HT2 antag onist, and ondansetron, a 5-HT3 antagonist, were assessed. In addition, the muscarinic agonist arecoline was evaluated for its potential cognitive ben efit in this model. It was found that WAY-100635 significantly reduced the cognitive impairment induced by MK801. Treatment with single doses of ritan serin, ondansetron, or arecoline in combination with MK801 did not result i n a cognitive impairment, indicating that these drugs attenuated the MK801 impairment. The combination of buspirone and MK801 resulted in an inability of the animals to complete the task. These results suggest that interactio ns between 5-HT and glutamate may mediate the beneficial effects of reducin g cognitive impairment and that 5-HT antagonists, especially selective 5-HT 1A antagonists, may be useful in treating AD. Further, it is indicated that the MK801 model of cognitive impairment may add to the armamentarium of to ols available to predict treatment efficacy in AD. (C) 1999 Academic Press.