Effects of age on antidepressant kinetics and memory in Fischer 344 rats

Experiments were conducted in young (3-4 months) and old (24-25 months) male Fischer 344 rats to assess the effects of amitriptyline, scopolamine, and zimelidine on short term memory using an eight arm radial maze paradigm. Kinetic analyses employing serial blood sampling were also conducted for amitriptyline and zimelidine in an attempt to determine if age-related deficits in performance could be related to changes in pharmacokinetics. In the maze, acquisition of performance was significantly decreased in old rats compared to young. Amitriptyline (5 mg/kg) produced a significant decrement in maze performance on day four of a five day testing period in both young and old rats, while scopolamine (1 mg/kg) produced an initial decrement on day one, followed by a return towards pre-treatment levels in these two age groups. Zimelidine (5 mg/kg) produced no performance decrement in either young or old rats. Kinetic analyses revealed an increased half-life, slower plasma clearance, and a larger volume of distribution of amitriptyline and zimelidine in old rats. Although the kinetic parameters in aged rats exhibited a change in the direction of a decreased ability to metabolize both drugs, this change was not of sufficient magnitude to produce an additive detrimental effect on maze performance.