Effects of acute and chronic administration of atomoxetine and methylphenidate on extracellular levels of noradrenaline, dopamine and serotonin in the prefrontal cortex and striatum of mice

Abstract

K. K. and Y. A. contributed equally to this work.Abbreviations used: 5-HT, serotonin; ADHD, attention-deficit/hyperactivity disorder; AUC, area under the curve; DA, dopamine; i.p., intraperitoneally; NA, noradrenaline; PBS, phosphate buffered saline. AbstractAcute administration of atomoxetine and methylphenidate, attention-deficit/hyperactivity disorder (ADHD) drugs, activates catecholaminergic systems in rat brain, but the effects of their chronic administration are not known. This study examined the effects of acute and chronic administration of ADHD drugs on the extracellular levels of noradrenaline (NA), dopamine (DA) and serotonin (5-HT), and the expression of the neuronal activity marker c-Fos in the prefrontal cortex and striatum of mice. Acute ADHD drugs increased NA and DA, but not 5-HT, levels in the prefrontal cortex of mice. Maximal effects of atomoxetine and methylphenidate were observed at 1 mg/kg and 3 mg/kg, respectively. At these doses, both drugs did not affect the spontaneous locomotor activity of mice. Chronic administration of atomoxetine 1 mg/kg and methylphenidate 3 mg/kg for 21 days also increased NA and DA, but not 5-HT, levels in the prefrontal cortex. The increases in NA levels induced by atomoxetine, but not methylphenidate, were reduced by chronic treatment. In contrast, acute and chronic administration of atomoxetine 1 mg/kg and methylphenidate 3 mg/kg did not affect the monoamine levels in the striatum. Acute and chronic atomoxetine 1 mg/kg and methylphenidate 3 mg/kg increased the expression of c-Fos in the prefrontal cortex, but not in the striatum, to a similar extent. These results suggest that acute and chronic administration of the ADHD drugs selectively activate the prefrontal catecholamine systems in mice.

Methylphenidate Modifies the Motion of the Circadian Clock

“…The data suggest that methylphenidate treatment renders the animals less susceptible to homeostatic sleep pressure as the animals are more awake over 24 h and are able to extend their active period by 1 h into the light period. Methylphenidate blocks both dopamine and norepinephrine transporters, increasing levels of these neurotransmitters in the synapse (Kodo et al, 2010), which can explain the increased waking as both monoamines are known to have wake and arousal promoting effects (Espana and Scammell, 2011). As a consequence, the animals initiate their main sleep period approximately an hour later with a higher sleep pressure than control.…”

“…It acts as a reuptake inhibitor at both dopamine and norepinephrine transporters, increasing levels of these neurotransmitters in the synapse (Kodo et al, 2010). While methylphenidate is quite effective at managing the inattention, impulsiveness, and hyperactivity associated with ADHD, it may not help the co-morbid sleep problems, and in fact methylphenidate may exacerbate these symptoms.…”

A Novel Translational Assay of Response Inhibition and Impulsivity: Effects of Prefrontal Cortex Lesions, Drugs Used in ADHD, and Serotonin 2C Receptor Antagonism

“…To enable crossspecies comparisons, we used the same dose ranges used in previous SSRTT studies in rats (Bari et al, 2009;Eagle et al, 2007). These doses ranges have been shown to be effective in other behavioral tasks in mice (Davis and Gould, 2007;Griffin et al, 2013) and lead to systematic changes in monoamine release in mouse mPFC assessed using microdialysis (Koda et al, 2010). Furthermore, the chosen dose range of methylphenidate gives rise in the mouse to approximate plasma levels obtained following therapeutic dosing in patients (Balcioglu et al, 2009).…”

Role of Social Encounter-Induced Activation of Prefrontal Serotonergic Systems in the Abnormal Behaviors of Isolation-Reared Mice

“…The neuronal-activity-marker c-Fos was determined 2 h after the encounter in the brains of male group-and isolation-reared mice, as described previously (Ago et al, 2011;Koda et al, 2010). Mice that were not exposed to an intruder were used as controls (Figure 2).…”

“…To address this issue, we used a cage that was divided into two compartments (large and small) by a mesh partition, and we examined the effects of intruder encounters on c-Fos expression and the levels of DA and 5-HT in the brains of resident mice reared in a group or in isolation. We used c-Fos expression to measure regional changes in brain activity (Koda et al, 2010;Kovács, 2008). As a control, we further examined female isolationreared mice, because they do not develop hyper-aggression, unlike male isolation-reared mice (Pinna et al, 2005(Pinna et al, , 2008.…”