Arecoline via miniosmotic pump improves AF64A-impaired radial maze performance in rats: a possible model of Alzheimer's disease.
Male Sprague-Dawley rats, preoperatively trained in a 1-h delay non-match-to-position radial maze task, received bilateral stereotaxic injections of a selective cholinotoxin, ethylcholine aziridinium ion (AF64A: 3 nmol/3 microliters/lateral ventricle). Animals treated with AF64A made significantly more total postdelay errors than vehicle controls. Sustained delivery, via miniosmotic pumps, of arecoline (0.1, 0.3, 1, 3, 10, or 30 mg/kg/day sc for 14 days) attenuated the AF64A-induced cognitive impairment in a dose-dependent manner, producing an inverted U-shaped dose-response function which was optimal at 1.0 mg/kg/day. Following these studies, choline acetyltransferase activity was significantly reduced in hippocampi extracted from the AF64A-treated rats, indicating successful cholinotoxicity. This paradigm may be useful as a possible screen for potential Alzheimer's disease therapeutic agents. This conclusion is supported by published reports of beneficial arecoline effects observed following 2-week intravenous infusions in patients with Alzheimer's disease (Soncrant, Raffaele, Asthana, Berardi, Morris, & Haxby, 1993).
Bartolomeo
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AC
CNS Disorders Division, Wyeth-Ayerst Research, Princeton, New Jersey 08543-8000, USA.
Morris
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H
Boast
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CA
D000544:Alzheimer Disease / Q000139:chemically induced / Q000503:physiopathology*; D000818:Animals; D001115:Arecoline / Q000494:pharmacology*; D001388:Aziridines / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D001931:Brain Mapping; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology; D002794:Choline / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D015918:Infusion Pumps, Implantable; D008297:Male; D018782:Maze Learning / Q000187:drug effects* / Q000502:physiology; D011939:Mental Recall / Q000187:drug effects* / Q000502:physiology; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009498:Neurotoxins / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012153:Retention, Psychology / Q000187:drug effects / Q000502:physiology
D001388:Aziridines; D018721:Muscarinic Agonists; D009498:Neurotoxins; D001115:Arecoline; C044894:ethylcholine aziridinium; D002794:Choline