Effects of atomoxetine and methylphenidate on attention and impulsivity in the 5-choice serial reaction time test.
Deficits in attention and response inhibition are apparent across several neurodegenerative and neuropsychiatric disorders for which current pharmacotherapy is inadequate. The 5-choice serial reaction time test (5-CSRTT), which originated from the continuous performance test (CPT) in humans, may serve as a useful translational assay for efficacy in these key behavioral domains. The selective norepinepherine reuptake inhibitor, atomoxetine, represents the first non-stimulant based drug approved for Attention Deficit Hyperactivity Disorder (ADHD) and has replaced methylphenidate (Ritalin) as the first line in pharmacotherapy for the treatment of ADHD. Methylphenidate and atomoxetine have different cortical and sub-cortical neurochemical signatures that could predict differences in cognitive and non-cognitive functions. The present experiments investigated the effects of acute methylphenidate and atomoxetine in male long Evans rats in the 5-choice serial reaction time (5CSRT) test that is hypothesized to serve as a model of vigilance and impulsivity behaviors associated with ADHD. Long Evans rats were trained to perform at 75% correct responses with fewer than 20% missed trials in the 5CSRT test (500 ms stimulus duration, 5 s inter-trial interval (ITI)). By varying the ITI (10, 7, 5, and 4 s) on drug test days, impulsivity (as defined by premature responses) was dramatically increased with a concomitant decrease in attention (percent correct). Subsequently, animals were treated with methylphenidate (2.5 and 5 mg/kg, i.p.) or atomoxetine (0.1, 0.5 and 1 mg/kg, i.p.) using this design. In Experiment 1, treatment with methylphenidate modestly improved overall attention but the highest dose of methylphenidate (5.0 mg/kg) significantly increased impulsivity. In contrast, treatment with atomoxetine induced a marked decrease in impulsivity whilst modestly improving overall attention. Interestingly, no effect was observed on measures of performance (e.g. motivation/sedation) with atomoxetine, whilst moderate hyperactivity (faster overall response latencies; magazine, correct, incorrect) was observed in the methylphenidate group. Those data suggest that the 5CSRT test can be used to differentiate stimulant and non-stimulant pharmacotherapies on measures of impulsivity.
Navarra
Rachel
R
Discovery Neuroscience, Wyeth Research, 500 Arcola Road, PA 19426 USA.
Graf
Radka
R
Huang
Youping
Y
Logue
Sheree
S
Comery
Thomas
T
Hughes
Zoe
Z
Day
Mark
M
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000818:Animals; D000069445:Atomoxetine Hydrochloride; D001288:Attention / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D002755:Choice Behavior / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D007175:Impulsive Behavior / Q000188:drug therapy*; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology*; D011437:Propylamines / Q000494:pharmacology*; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans; D011930:Reaction Time / Q000187:drug effects*
D018759:Adrenergic Uptake Inhibitors; D000697:Central Nervous System Stimulants; D011437:Propylamines; D008774:Methylphenidate; D000069445:Atomoxetine Hydrochloride