Understanding comorbid ADHD and cocaine abuse: consequences of adolescent medication in an animal model

Attention-deficit/hyperactivity disorder (ADHD) is highly comorbid with substance use disorders, particularly cocaine. Preclinical studies using the well-validated Spontaneously Hypertensive Rat (SHR) model of ADHD suggest that adolescent treatment with the stimulant methylphenidate increases cocaine abuse risk in adulthood, highlighting the need to identify alternative medications for teenagers with ADHD. Experiments 1-4 tested the hypothesis that atomoxetine, a non-stimulant that improves prefrontal cortex functioning in adolescent SHR, would not increase cocaine abuse risk. The speed to acquire cocaine self-administration, the efficacy and motivating influence of cocaine reinforcement, and reactivity to cocaine cues in adulthood following discontinuation of adolescent atomoxetine treatment were examined in male SHR and two genetic control strains: inbred Wistar-Kyoto (WKY) and outbred Wistar (WIS). Because atomoxetine is not always as clinically efficacious as methylphenidate, Experiments 5-9 tested the hypothesis that an alternative stimulant, d-amphetamine, would improve cognitive performance in adolescent SHR during a strategy set-shifting task and not increase cocaine abuse risk in adult SHR after adolescent d-amphetamine was discontinued. Across experiments, adult SHR acquired cocaine self-administration faster than control strains and also were more sensitive to cocaine’s reinforcing and motivating influence and more reactive to cocaine cues. As hypothesized, adolescent atomoxetine did not increase any measure of cocaine abuse risk in adult SHR and modestly reduced SHR’s reactivity to cocaine cues. In WKY control, however, adolescent atomoxetine accelerated acquisition of cocaine self-administration. d-Amphetamine improved set-shifting deficits in adolescent SHR, demonstrating pro-cognitive effects as hypothesized. When self-administration was acquired, cocaine intake was lower in adult SHR that received adolescent d-amphetamine compared to vehicle-treated SHR, consistent with the hypothesis. Adolescent d-amphetamine slowed acquisition and reduced the efficacy and motivating influence of cocaine reinforcement in WIS control, but accelerated acquisition in WKY control. Collectively, these results highlight the heuristic value of SHR in evaluating comorbid ADHD and cocaine abuse risk, and suggest that atomoxetine and d-amphetamine may be safer medications than methylphenidate for teenagers with ADHD. However, findings in control strains emphasize the need for accurate ADHD diagnosis, as the long-term consequences of treatment could be favorable (d-amphetamine in WIS) or unfavorable (atomoxetine and d-amphetamine in WKY) in misdiagnosed individuals