Gregg D. Cappon Richard H. Alper, Brian Bush, Donald Newgreen, Edmund Kadyszewski, Greg Finch

Pfizer Global Research and Development, Groton, CT; Pfizer Global Research and Development, Sandwich, UK

Introduction and Objectives: Antimuscarinics are first-line pharmacotherapy for overactive bladder (OAB). Central nervous system (CNS) cholinergic neurotransmission is involved in cognition, and CNS–permeable antimuscarinics scopolamine and oxybutynin affect memory. We evaluated the effect of tolterodine, an antimuscarinic for OAB, in a mouse passive-avoidance (PA) model of memory. Mice were chosen because mice and humans, but not rats, form the active metabolite of tolterodine, DD01.

Methods: For the PA test, male mice were placed in the illuminated half of an apparatus separated into light and dark chambers. Upon entering the dark chamber, mice received a mild electric shock. After initial experiences, mice either learned not to cross into the dark chamber or to take longer to do so. Two training trials were run in a single day (1-h intertrial interval) followed by a retention (memory) test about 24 hours later. Mice (n=24/group) were given tolterodine tartrate (1 or 3 mg/kg PO) or scopolamine (3 mg/kg IP) approximately 20 minutes before the first PA training trial. Satellite groups of 5 mice were given tolterodine, and blood was collected at the time of maximum concentration (T_max; approximately 0.5 h postdose) for determination of the active moiety (tolterodine and DD01). This study was funded by Pfizer Inc.

Results: In the PA 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 (Table). Total free active moiety at 0.5 hours postdose (approximate T_max) was 0.74 and 7.99 nM at 1 and 3 mg/kg tolterodine, respectively (approximately 0.5- and 6-fold human maximum concentration achieved with the 4-mg extended-release formulation).

Conclusions: At a dose exceeding therapeutic exposure, tolterodine had no effect on memory in the mouse PA model, indicating that tolterodine does not disrupt cognitive function in this testing paradigm.

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