The scopolamine-reversal paradigm in rats and monkeys: the importance of computer-assisted operant-conditioning memory tasks for screening drug candidates.
BACKGROUND
The scopolamine-reversal model is enjoying a resurgence of interest in clinical studies as a reversible pharmacological model for Alzheimer's disease (AD). The cognitive impairment associated with scopolamine is similar to that in AD. The scopolamine model is not simply a cholinergic model, as it can be reversed by drugs that are noncholinergic cognition-enhancing agents.


OBJECTIVE
The objective of the study was to determine relevance of computer-assisted operant-conditioning tasks in the scopolamine-reversal model in rats and monkeys.


METHODS
Rats were evaluated for their acquisition of a spatial reference memory task in the Morris water maze. A separate cohort was proficient in performance of an automated delayed stimulus discrimination task (DSDT). Rhesus monkeys were proficient in the performance of an automated delayed matching-to-sample task (DMTS).


RESULTS
The AD drug donepezil was evaluated for its ability to reverse the decrements in accuracy induced by scopolamine administration in all three tasks. In the DSDT and DMTS tasks, the effects of donepezil were delay (retention interval)-dependent, affecting primarily short delay trials. Donepezil produced significant but partial reversals of the scopolamine-induced impairment in task accuracies after 2 mg/kg in the water maze, after 1 mg/kg in the DSDT, and after 50 microg/kg in the DMTS task.


CONCLUSIONS
The two operant-conditioning tasks (DSDT and DMTS) provided data most in keeping with those reported in clinical studies with these drugs. The model applied to nonhuman primates provides an excellent transitional model for new cognition-enhancing drugs before clinical trials.
Alzheimer's Research Center, Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA 30912, USA. jbuccafu@mcg.edu
Jerry J
JJ
Buccafusco
Alvin V
AV
Terry
Scott J
SJ
Webster
Daniel
D
Martin
Elizabeth J
EJ
Hohnadel
Kristy A
KA
Bouchard
Samantha E
SE
Warner
D000375:Aging / Q000523:psychology; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003201:Computers; D003216:Conditioning, Operant / Q000187:drug effects*; D004193:Discrimination Learning / Q000187:drug effects; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D007189:Indans / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects*; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans; D017208:Rats, Wistar; D012601:Scopolamine / Q000494:pharmacology*
D002800:Cholinesterase Inhibitors; D007189:Indans; D018727:Muscarinic Antagonists; D010880:Piperidines; D000077265:Donepezil; D012601:Scopolamine