Effect of methylphenidate on dopamine/DARPP signalling in adult, but not young, mice.
Methylphenidate (MPH), a dopamine uptake inhibitor, is the most commonly prescribed drug for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children. We examined the effect of MPH on dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa (DARPP-32) phosphorylation at Thr34 (PKA-site) and Thr75 (Cdk5-site) using neostriatal slices from young (14-15- and 21-22-day-old) and adult (6-8-week-old) mice. MPH increased DARPP-32 Thr34 phosphorylation and decreased Thr75 phosphorylation in slices from adult mice. The effect of MPH was blocked by a dopamine D1 antagonist, SCH23390. In slices from young mice, MPH did not affect DARPP-32 phosphorylation. As with MPH, cocaine stimulated DARPP-32 Thr34 phosphorylation in slices from adult, but not from young mice. In contrast, a dopamine D1 agonist, SKF81297, regulated DARPP-32 phosphorylation comparably in slices from young and adult mice, as did methamphetamine, a dopamine releaser. The results suggest that dopamine synthesis and the dopamine transporter are functional at dopaminergic terminals in young mice. In contrast, the lack of effect of MPH in young mice is likely attributable to immature development of the machinery that regulates vesicular dopamine release.
Fukui
Ryuichi
R
Department of Physiology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan.
Svenningsson
Per
P
Matsuishi
Toyojiro
T
Higashi
Hideho
H
Nairn
Angus C
AC
Greengard
Paul
P
Nishi
Akinori
A
D000375:Aging / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D001552:Benzazepines / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004347:Drug Interactions; D015151:Immunoblotting / Q000379:methods; D066298:In Vitro Techniques; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology; D008774:Methylphenidate / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D013912:Threonine / Q000378:metabolism
D001552:Benzazepines; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D008774:Methylphenidate; D013912:Threonine; D008694:Methamphetamine; C067113:SK&F 81297; D003042:Cocaine; D004298:Dopamine