Performance on a strategy set shifting task during adolescence in a genetic model of attention deficit/hyperactivity disorder: Methylphenidate vs. atomoxetine treatments

Abstract

Research examining medication effects on set shifting in teens with attention deficit/hyperactivity disorder (ADHD) is lacking. An animal model of ADHD may be useful for exploring this gap. The Spontaneously Hypertensive Rat (SHR) is a commonly used animal model of ADHD. SHR and two comparator strains, Wistar-Kyoto (WKY) and Wistar (WIS), were evaluated during adolescence in a strategy set shifting task under conditions of a 0-sec or 15-sec delay to reinforcer delivery. The task had three phases: initial discrimination, set shift and reversal learning. Under 0-sec delays, SHR performed as well as or better than WKY and WIS. Treatment with 0.3 mg/kg/day atomoxetine had little effect, other than to modestly increase trials to criterion during set shifting in all strains. Under 15-sec delays, SHR had longer lever press reaction times, longer latencies to criterion and more trial omissions than WKY during set shifting and reversal learning. These deficits were not reduced systematically by 1.5 mg/kg/day methylphenidate or 0.3 mg/kg/day atomoxetine. Regarding learning in SHR, methylphenidate improved initial discrimination, whereas atomoxetine improved set shifting but disrupted initial discrimination. During reversal learning, both drugs were ineffective in SHR, and atomoxetine made reaction time and trial omissions greater in WKY. Overall, WIS performance differed from SHR or WKY, depending on phase. Collectively, a genetic model of ADHD in adolescent rats revealed that neither methylphenidate nor atomoxetine mitigated all deficits in SHR during the set shifting task. Thus, methylphenidate or atomoxetine monotherapy may not mitigate all set shift task-related deficits in teens with ADHD.

Adolescent d -amphetamine treatment in a rodent model of ADHD: Pro-cognitive effects during adolescence and cocaine abuse risk during adulthood

“…Strategy set shifting in adolescence 2.4.1 Habituation-An operant version of the strategy set shifting task was used [22,52]. On P28, WKY treated with vehicle (n=9) or d-amphetamine (n=9), WIS treated with vehicle (n=9) or d-amphetamine (n=9), and SHR treated with vehicle (n=10) or d-amphetamine (n=12), received 20 chocolate-flavored pellets in their home cages, to habituate rats to the novel food.…”

“…Rats were individually housed in plastic cages with Aspen bedding in a temperature-(21-23°C) and light-(07:30 hours on; 19:30 hours off) controlled vivarium]. From P28-P55, constituting the rat adolescent period [61], food was restricted to achieve ~90% of a growth-adjusted free-feeding body weight to facilitate lever responding for food reinforcement during the strategy set-shifting task, and to mimic conditions of past comparator studies [22,30,[33][34][35]62]. Animals had free access to water throughout experiments and to food after P55.…”

“…Trial contingencies were otherwise identical to those of the initial set and set shift phases. Training on reversal learning continued until rats made 10 consecutive correct responses [22,52]. To preserve catheter patency on weekends and holidays, catheters were filled with 0.08 ml of a locking solution consisting of glycerol (Sigma-Aldrich, St. Louis, MO, USA) and heparin (1000 mg/ml) in a 3:1 ratio.…”

“…SHR exhibit the core symptoms of ADHD, such as impulsivity, hyperactivity, inattention, increased novelty seeking, poor working memory and behavioral inflexibility [19][20][21][22][23][24][25]. Importantly, these deficits are unrelated to hypertension in SHR [24,[26][27][28], and can be improved by ADHD medications [22,[29][30][31]. The WKY, which is the progenitor strain of the SHR, does not exhibit hyperactivity, impulsivity, or hypertension, and is frequently used as an inbred control strain [26].…”

“…Trial contingencies were otherwise identical to the initial set formation phase. Training on the set shift phase continued until rats made 10 consecutive correct responses [22,52].…”