Age-related changes in the pharmacological improvement of retention in senescence accelerated mouse (SAM)

The P/8 line of the senescence accelerated mouse (SAM) model exhibits characteristics of aging early in its lifespan including an early onset of impaired learning and memory which becomes progressively worse with age. Age-matched controls of the R/1 line do not show impaired learning and memory. We report age-related changes in the drug dosage needed to improve 1 week retention in the P/8 but not R/1 line. The results indicate that 8-month-old P/8 mice show a reduced sensitivity to memory enhancing doses of cholinomimetics and an increased sensitivity to a serotonin antagonist compared to 4-month-old mice. By 12 months of age, improvement of retention required still higher doses of cholinomimetics and even lower doses of the serotonin antagonist. Higher doses of an opioid antagonist and a dopamine agonist were needed to improve retention in 12-month-old mice. A GABA antagonist and an alpha noradrenergic agonist improved retention at the same dose in mice 4, 8, and 12 months of age.