Pharmacokinetic and pharmacodynamic analysis of d-amphetamine in an attention task in rodents

Abstract

Amphetamine is a common therapeutic agent for alleviating the core symptoms associated with attention-deficit hyperactivity disorder (ADHD) in children and adults. The current study used a translational model of attention, the five-choice serial reaction time (5-CSRT) procedure with rats, to examine the time-course effects of d-amphetamine. Effects of different dosages of d-amphetamine were related to drug-plasma concentrations, fashioned after comprehensive pharmacokinetic/pharmacodynamic assessments that have been employed in clinical investigations. We sought to determine whether acute drug-plasma concentrations that enhance performance in the 5-CSRT procedure are similar to those found to be therapeutic in patients diagnosed with ADHD. Results from the pharmacokinetic/pharmacodynamic assessment indicate that d-amphetamine plasma concentrations associated with improved performance on the 5-CSRT procedure overlap with those that have been reported to be therapeutic in clinical trials. The current findings suggest that the 5-CSRT procedure may be a useful preclinical model for predicting the utility of novel ADHD therapeutics and their effective concentrations.

Fig. 1

The average percentage of correct responses (upper left), trials with an omission (upper right), latency to respond after sample stimulus onset (lower left), and number of ITI responses (lower right) are presented as a function of d-amphetamine testing time (min). Within each panel there are five functions representing the vehicle or different doses of d-amphetamine (filled square for saline, open upward triangle for 0.1 mg/kg, open downward triangle for 0.3 mg/kg, open circle for 1.0 mg/kg, and open diamond for 1.7 mg/kg). Error bars are presented as standard error of the mean (SEM); where bars are absent they are encompassed by the symbol. Significant effects are denoted by a single asterisk.

Fig. 2

The average drug plasma levels (ng/ml) are presented as a function of time (mins) after 1.0 mg/kg d-amphetamine administration (left panel). Pharmacokinetic parameters listed within the left panel are the mean values with standard deviations within parentheses. The relation between the effects of 1.0 mg/kg d-amphetamine administration on the percentage of correct responses and the different d-amphetamine plasma concentrations engendered is depicted by a hysteresis plot in the right panel. The arrows on the function indicate increases in testing time from 15 min (rightmost open circle) to 240 min (leftmost open circle). The shaded region indicates the range of performance during vehicle-only tests. Error bars are presented as SEM in the left panel; where bars are absent they are encompassed by the symbol.