Tolterodine does not affect memory assessed by passive-avoidance response test in mice.
Antimuscarinics are first-line pharmacotherapy for the treatment of overactive bladder. However, because central nervous system cholinergic neurotransmission is involved in cognition, and the central nervous system-permeable antimuscarinics scopolamine and oxybutynin affect memory, cognitive impairment has been noted as a possible side effect of these drugs. We evaluated the effect of tolterodine, an antimuscarinic for overactive bladder, in a mouse passive-avoidance model of memory. Mice were chosen because like humans, mice but not rats, form the pharmacologically active 5-hydroxymethyl metabolite of tolterodine, DD01. In the passive-avoidance test, tolterodine at 1 or 3 mg/kg had no effect on memory; the latency to cross and percentage of animals crossing were comparable to controls. In contrast, scopolamine induced a memory deficit; the latency to cross was decreased, and the number of animals crossing was increased. Therefore, at a dose exceeding therapeutic exposure by six-fold, tolterodine had no effect on memory in the mouse passive-avoidance model, indicating that tolterodine does not disrupt cognitive function in this testing paradigm.
Cappon
Gregg D
GD
Pfizer Global Research and Development, Drug Safety Research and Development, Groton, CT 06340, United States. gregg.d.cappon@pfizer.com
Bush
Brian
B
Newgreen
Donald
D
Finch
Gregory L
GL
Alper
Richard H
RH
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects*; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D003408:Cresols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D008297:Male; D008568:Memory / Q000187:drug effects*; D051379:Mice; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D010665:Phenylpropanolamine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D011897:Random Allocation; D012601:Scopolamine / Q000633:toxicity; D013045:Species Specificity; D000068737:Tolterodine Tartrate
D001559:Benzhydryl Compounds; D003408:Cresols; D018727:Muscarinic Antagonists; D010665:Phenylpropanolamine; D000068737:Tolterodine Tartrate; D012601:Scopolamine