APP23 mice are a promising model of Alzheimer's disease, expressing several histopathological, cognitive and behavioural hallmarks of the human condition. A valid animal model should respond to therapeutic interventions in an equivalent manner as human patients. To further validate the APP23 model, we examined whether cognitive deficits could be antagonised by donepezil, rivastigmine, galantamine or memantine, which are approved drugs for symptomatic treatment of dementia. Animals were tested at an age at which untreated APP23 mice display severe deficits in visual-spatial learning. Four-month-old APP23 mice and control littermates were administered donepezil (0.3 or 0.6 mg kg(-1)), rivastigmine (0.5 or 1.0 mg kg(-1)), galantamine (1.25 or 2.5 mg kg(-1)), memantine (2 or 10 mg kg(-1)) or saline through daily i.p. injections. After 1 week of treatment, acquisition phase commenced, with daily treatment continuing during cognitive testing. All cholinesterase inhibitors reduced cognitive deficits with the following optimal daily doses: galantamine 1.25 mg kg(-1), rivastigmine 0.5 mg kg(-1) and donepezil 0.3 mg kg(-1). Higher dosages often did not exert beneficial effects in accordance with inverted U-shaped dose-response curves described for cholinomimetics. Symptomatic efficacy of memantine on cognition was mild, with significant amelioration manifesting during probe trial. This is the first study to simultaneously evaluate the efficacy of therapeutically relevant doses of these four compounds in one particular learning and memory paradigm, being the Morris water maze. The fact that symptomatic intervention was able to diminish cognitive impairment, substantially adds to the validity of the APP23 model as a valuable tool to evaluate future therapeutic approaches.