Arecoline via Miniosmotic Pump Improves AF64A-Impaired Radial Maze Performance in Rats: A Possible Model of Alzheimer's Disease

doi:10.1006/nlme.1997.3786

Neurobiology of Learning and Memory

Volume 68, Issue 3, November 1997, Pages 333-342

https://doi.org/10.1006/nlme.1997.3786 Get rights and content

Abstract

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 μl/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).

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Citation Excerpt :
In fact, the DFP regimen we used had already reduced brain levels of AChE to only 13% of control enzyme activity just prior to the initiation of withdrawal. The dose we chose for arecoline was based upon those shown to improve memory in behavioral tasks performed by rats [5, 28]. This insured that arecoline, as we employed it, was compatible with higher cognitive activities, and therefore, unlikely to induce untoward reactions in the animals.
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^☆: The authors thank Dr. Gary Wenk and Dr. Robert Stackman for their technical advice on establishing the choline acetyltransferase assay. Thanks are also extended to Cathy Hoffman, Stephanie Maurer, and Fran Storch for their assistance in maze training, surgeries, maze testing, and brain harvesting. Thanks are extended to Mike Weaver, Charlie Vorhees, and Ed Godfrey for their work in building and maintaining the radial maze and to Bob LaForge for his work in generating the computer program and electronic interfaces which track and record maze activity. The authors thank Dr. Frank Shen and Tammy Coffey for their statistical analysis of the data. Finally, thanks are extended to Erica DiPaola for her work in preparing this manuscript.

^☆☆: Address reprint requests to Carl Boast, Ph.D., CNS Disorders Division, Wyeth-Ayerst Research, CN 8000, Princeton, NJ 08543-8000.

^★: H. Y. Meltzer, Ed.

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BRIEF REPORTArecoline via Miniosmotic Pump Improves AF64A-Impaired Radial Maze Performance in Rats: A Possible Model of Alzheimer's Disease☆,☆☆,★

Abstract

Clinical pharmacokinetics of arecoline in subjects with Alzheimer's disease

Clinical Pharmacology and Therapeutics

Acute and chronic arecoline: Effects on a scopolamine-induced deficit in complex maze learning

Pharmacology, Biochemistry and Behavior

AF64A-induced working memory impairment: Behavioral, neurochemical and histological correlates

Brain Research

Hemicholinium-3 prevents the working memory impairments and the cholinergic hypofunction induced by ethylcholine aziridinium ion (AF64A)

Brain Research

Reversible cholinergic changes induced by AF64A in rat hippocampus and possible septal compensatory effects

Neuropharmacology

(±)-cis-2-Methyl-spiro(1,3-oxathiolane-5,3′) quninuclide (AF102B): A new M1

Neuroscience Letters

M1 agonists for the treatment of Alzheimer's disease. Novel properties and clinical update

Annals of the New York Academy of Sciences

Ethylcholine aziridinium (AF64A; ECMA) and other potential cholinergic neuron-specific neurotoxins

Psychopharmacology: The third generation of progress

Impaired phosphoinositide hydrolysis in Alzheimer's disease brain

Neurobiology of Aging

Regional alterations in M1 muscarinic receptor-G protein coupling in Alzheimer's disease

Journal of Neuropathology and Experimental Neurology

Intracerebroventricular administration of ethylcholine mustard aziridinium ion (AF64A) reduces release of acetylcholine from rat hippocampal slices

Neuropharmacology

Time course of ethylcholine aziridinium ion (AF64A)-induced cholinotoxicity in vitro

Neuropharmacology

Cognitive test performance in detecting, staging and tracking Alzheimer's disease

Archives of Neurology

Protein measurement with the folin phenol reagent

Journal of Biological Chemistry

BRIEF REPORT
Arecoline via Miniosmotic Pump Improves AF64A-Impaired Radial Maze Performance in Rats: A Possible Model of Alzheimer's Disease☆,☆☆,★

(±)-cis-2-Methyl-spiro(1,3-oxathiolane-5,3′) quninuclide (AF102B): A new M₁