Flumazenil and tacrine increase the effectiveness of ondansetron on scopolamine-induced impairment of spatial learning in rats.
BACKGROUND
Cholinergic receptor blockade produces memory deficits in animal models. These deficits can be prevented by 5-HT3 receptor antagonists, such as ondansetron, which increases acetylcholine release. We investigated the effects on cognitive performance of combined treatments of ondansetron with either flumazenil, a GABA(A) receptor benzodiazepine site antagonist, or tacrine, a cholinesterase inhibitor, which are also able to prevent scopolamine-induced cognitive impairment.


METHODS
Spatial learning and memory was assessed by studying the effects of single and combined treatments on acquisition and retention of the Morris water maze task in rats.


RESULTS
Scopolamine (0.6 mg/kg) induced significant learning and retention deficits. Both ondansetron (0.1 microg/kg) and tacrine (3 mg/kg) partially prevented the scopolamine-induced learning deficit. A full reversal was only found after the combined treatment of ondansetron with flumazenil (10 mg/kg) and also after tacrine in combination with ondansetron. Likewise, scopolamine-induced retention deficit was fully counteracted by the combined treatment of ondansetron with either flumazenil or tacrine, and only partially by any of the single treatments tested.


CONCLUSIONS
The scopolamine-induced impairment of learning and retention in the water maze is fully prevented by ondansetron when given in combination with either flumazenil or tacrine, suggesting that both combined treatments result in a potentiated cholinergic function and may constitute the basis of a new therapy for cognitive disorders.
Diez-Ariza
M
M
Department of Pharmacology, School of Medicine, University of Navarra, Irunlarrea 1, 31008 Pamplona, Spain.
Redondo
C
C
García-Alloza
M
M
Lasheras
B
B
Del Río
J
J
Ramírez
M J
MJ
D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D005442:Flumazenil / Q000494:pharmacology*; D007858:Learning / Q000187:drug effects*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D018727:Muscarinic Antagonists / Q000633:toxicity; D017294:Ondansetron / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects*; D012601:Scopolamine / Q000633:toxicity; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013619:Tacrine / Q000494:pharmacology*
D002800:Cholinesterase Inhibitors; D018727:Muscarinic Antagonists; D011963:Receptors, GABA-A; D012702:Serotonin Antagonists; D005442:Flumazenil; D017294:Ondansetron; D013619:Tacrine; D012601:Scopolamine