5HT antagonists attenuate MK801-impaired radial arm maze performance in rats.
Glutamatergic hypofunction occurs in Alzheimer's disease (AD). MK801, a noncompetitive blocker of glutamate N-methyl-D-aspartate receptors, was used to disrupt the cognitive performance of rats trained on a delayed nonmatching to sample radial maze task. Drugs which act by blocking serotonin (5-HT) receptors were evaluated for their ability to reduce the cognitive impairment produced by MK801. Specifically, WAY-100635, a selective 5-HT1A receptor antagonist, buspirone, a 5-HT1A partial agonist, ritanserin, a 5-HT2 antagonist, and ondansetron, a 5-HT3 antagonist, were assessed. In addition, the muscarinic agonist arecoline was evaluated for its potential cognitive benefit in this model. It was found that WAY-100635 significantly reduced the cognitive impairment induced by MK801. Treatment with single doses of ritanserin, ondansetron, or arecoline in combination with MK801 did not result in 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 interactions between 5-HT and glutamate may mediate the beneficial effects of reducing cognitive impairment and that 5-HT antagonists, especially selective 5-HT1A antagonists, may be useful in treating AD. Further, it is indicated that the MK801 model of cognitive impairment may add to the armamentarium of tools available to predict treatment efficacy in AD.
Boast
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CNS Disorders Division, Wyeth-Ayerst Research, CN 8000, Princeton, New Jersey, 08543-8000, USA. boastc@war.wyeth.com
Bartolomeo
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AC
Morris
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Moyer
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JA
D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D001115:Arecoline / Q000627:therapeutic use; D003072:Cognition Disorders / Q000139:chemically induced* / Q000188:drug therapy; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000009:adverse effects* / Q000378:metabolism*; D004357:Drug Synergism; D005971:Glutamates / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D018721:Muscarinic Agonists / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000009:adverse effects* / Q000378:metabolism*; D010879:Piperazines / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012702:Serotonin Antagonists / Q000494:pharmacology* / Q000627:therapeutic use
D005971:Glutamates; D018721:Muscarinic Agonists; D018696:Neuroprotective Agents; D010879:Piperazines; D011725:Pyridines; D012702:Serotonin Antagonists; D001115:Arecoline; D016291:Dizocilpine Maleate; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide