Deleterious mutations in patchd1 domain containing 1 (PTCHD1) gene have been identified in patients with intellectual disability and/or autism spectrum disorder (ASD). To clarify the causal relationship between Ptchd1 deficiency and behavioral defects relevant to neurodevelopmental disorders, we generated global Ptchd1 knockout (KO) mice. Ptchd1 KO mice displayed hyperlocomotion, increased impulsivity, and lower recognition memory, which resemble attention-deficit hyperactivity disorder (ADHD)-like behaviors. Acute or chronic treatment with atomoxetine ameliorated almost all behavioral deficits in Pthcd1 KO mice. We next determined possible involvement of the kynurenine pathway (KP) metabolites in neurodevelopmental disorders in Ptchd1 KO mice and assessed the potential of KP metabolites as biomarkers for ADHD and/or ASD. Ptchd1 KO mice showed drastic changes in KP metabolite concentrations in the serum and the brain, indicating that the activated KP is associated with ADHD-like behaviors. Our findings indicate that Ptchd1 KO mice can be used as an animal model of human ADHD and/or ASD, and KP metabolites are potential diagnostic biomarkers for neurodevelopmental disorders.

Atomoxetine (ATX) is a non-stimulant drug used in the treatment of attention-deficit/hyperactivity disorder (ADHD) and is a selective norepinephrine reuptake inhibitor. It has been shown that ATX has additional effects beyond the inhibition of norepinephrine reuptake, affecting several signal transduction pathways and alters gene expression. Here, we study alterations in oxidative stress and mitochondrial function in human differentiated SH-SY5Y cells exposed over a range of concentrations of ATX. We found that the highest concentrations of ATX in neuron-like cells, caused cell death and an increase in cytosolic and mitochondrial reactive oxygen species, and alterations in mitochondrial mass, membrane potential and autophagy. Interestingly, the dose of 10 μM ATX increased mitochondrial mass and decreased autophagy, despite the induction of cytosolic and mitochondrial reactive oxygen species. Thus, ATX has a dual effect depending on the dose used, indicating that ATX produces additional active therapeutic effects on oxidative stress and on mitochondrial function beyond the inhibition of norepinephrine reuptake.

Individuals with attention-deficit/hyperactivity disorder tend to make risker choices during probabilistic-discounting procedures. Thus, how common attention-deficit/hyperactivity disorder medications affect probabilistic discounting is of interest. In general, d-amphetamine increases risk-taking while atomoxetine has produced mixed effects in rats. Results from previous studies may result from genetic factors. Lewis and F344 rats have neurochemical differences that may be relevant to probabilistic discounting and how drugs affect such behavior. In this study, we evaluated dose-dependent effects of d-amphetamine and atomoxetine on probabilistic discounting of Lewis and F344. Male Lewis and F344 chose between one food pellet delivered 100% of the time and three food pellets delivered following decreasing probabilities of delivery (i.e. 100%, 66.7%, 33.3%, 16.5%, and 8.25%). Saline, d-amphetamine (0.1-1.8 mg/kg), and atomoxetine (0.1-7.8 mg/kg) were tested acutely. Lewis and F344 did not differ in choice at baseline. d-Amphetamine increased risky choice for both rat strains at low-to-moderate doses, although it did so at a lower dose (0.1 and 0.3 mg/kg) for F344 as compared to Lewis (0.3 mg/kg only). At high doses (1.0 and 1.8 mg/kg), d-amphetamine disrupted choice, increased frequencies of omitted trials, and reduced reinforcer sensitivity. Although atomoxetine increased frequencies of omitted trials at high doses (5.6 and 7.8 mg/kg), it had no effect on probabilistic discounting for either rat strain. Although Lewis and F344 differ in various types of impulsivity (i.e. motor, choice), with Lewis being the more impulsive of the two, the present results suggest that Lewis and F344 do not differ in risk-based decision-making. Effects of d-amphetamine on probabilistic discounting may be biology-dependent and differ from effects of atomoxetine.

Introduction: The prevalence of Attention-Deficit/Hyperactivity Disorder (ADHD) has risen over the last two decades, with a corresponding increase in the cost of its medication. Drug utilization studies in South Africa focusing on ADHD are limited. Areas covered: The primary aim was to determine the cost of methylphenidate and atomoxetine (used for ADHD). The Intercontinental Marketing Service (IMS) database which contains data of the private healthcare sector was interrogated from 2013 to 2016 (48-month period) focussing on methylphenidate and atomoxetine. Drug consumption was expressed in number of DDDs, DDDs/1000 inhabitants/day and cost in Rands. Expert opinion: Methylphenidate-containing products constituted a considerably higher percentage of the market share when compared to atomoxetine (90.30% versus 9.70%). The DDD/1000 inhabitants/day for methylphenidate was 6.010 with an annual cost for R266 691 778 in 2013, which increased to 7.827 DDDs/1000 inhabitants/day with an annual cost of R436 041 506 in 2016. Consumption of both methylphenidate and atomoxetine increased from 2013 to 2016. There was a preference for long-acting extended-release methylphenidate tablets even though the unit costs were higher when compared to the short-acting formulations. Despite increases in unit costs, the spend in South Africa showed an upward trend for methylphenidate and atomoxetine.

Elucidation of how neuromodulators influence motivated behaviors is a major challenge of neuroscience research. It has been proposed that the locus-cœruleus-norepinephrine system promotes behavioral flexibility and provides resources required to face challenges in a wide range of cognitive processes. Both theoretical models and computational models suggest that the locus-cœruleus-norepinephrine system tunes neural gain in brain circuits to optimize behavior. However, to the best of our knowledge, empirical proof demonstrating the role of norepinephrine in performance optimization is scarce. Here, we modulated norepinephrine transmission in monkeys performing a Go/No-Go discrimination task using atomoxetine, a norepinephrine-reuptake inhibitor. We tested the optimization hypothesis by assessing perceptual sensitivity, response bias, and their functional relationship within the framework of the signal detection theory. We also manipulated the contingencies of the task (level of stimulus discriminability, target stimulus frequency, and decision outcome values) to modulate the relationship between sensitivity and response bias. We found that atomoxetine increased the subject's perceptual sensitivity to discriminate target stimuli regardless of the task contingency. Atomoxetine also improved the functional relationship between sensitivity and response bias, leading to a closer fit with the optimal strategy in different contexts. In addition, atomoxetine tended to reduce reaction time variability. Taken together, these findings support a role of norepinephrine transmission in optimizing response strategy.