Long-term exposure to oral methylphenidate or dl-amphetamine mixture in peri-adolescent rhesus monkeys: effects on physiology, behavior, and dopamine system development.
The stimulants methylphenidate and amphetamine are used to treat children with attention deficit/hyperactivity disorder over important developmental periods, prompting concerns regarding possible long-term health impact. This study assessed the effects of such a regimen in male, peri-adolescent rhesus monkeys on a variety of cognitive/behavioral, physiological, and in vivo neurochemical imaging parameters. Twice daily (0900 and 1200 hours), for a total of 18 months, juvenile male monkeys (8 per group) consumed either an unadulterated orange-flavored solution, a methylphenidate solution, or a dl-amphetamine mixture. Doses were titrated to reach blood/plasma levels comparable to therapeutic levels in children. [¹¹C]MPH and [¹¹C]raclopride dynamic PET scans were performed to image dopamine transporter and D₂-like receptors, respectively. Binding potential (BP(ND)), an index of tracer-specific binding, and amphetamine-induced changes in BP(ND) of [¹¹C]raclopride were estimated by kinetic modeling. There were no consistent differences among groups on the vast majority of measures, including cognitive (psychomotor speed, timing, inhibitory control, cognitive flexibility), general activity, physiological (body weight, head circumference, crown-to-rump length), and neurochemical (ie, developmental changes in dopamine transporter, dopamine D₂ receptor density, and amphetamine-stimulated dopamine release were as expected). Cytogenetic studies indicated that neither drug was a clastogen in rhesus monkeys. Thus, methylphenidate and amphetamine at therapeutic blood/plasma levels during peri-adolescence in non-human primates have little effect on physiological or behavioral/cognitive development.
Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Paul L
PL
Soto
Kristin M
KM
Wilcox
Yun
Y
Zhou
Anil
A
Kumar
Nancy A
NA
Ator
Mark A
MA
Riddle
Dean F
DF
Wong
Michael R
MR
Weed
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D002869:Chromosome Aberrations / Q000187:drug effects; D003627:Data Interpretation, Statistical; D004298:Dopamine / Q000502:physiology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D056344:Executive Function / Q000187:drug effects; D006128:Growth / Q000187:drug effects; D008253:Macaca mulatta; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D009420:Nervous System / Q000000981:diagnostic imaging / Q000254:growth & development*; D049268:Positron-Emission Tomography; D011930:Reaction Time / Q000187:drug effects; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D012646:Self Administration; D012854:Sister Chromatid Exchange / Q000187:drug effects
D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D017448:Receptors, Dopamine D2; D008774:Methylphenidate; D000661:Amphetamine; D004298:Dopamine