TY - JOUR
T1 - Long-term exposure to oral methylphenidate or dl-amphetamine mixture in peri-adolescent rhesus monkeys
T2 - Effects on physiology, behavior, and dopamine system development
AU - Soto, Paul L.
AU - Wilcox, Kristin M.
AU - Zhou, Yun
AU - Ator, Nancy A.
AU - Riddle, Mark A.
AU - Wong, Dean F.
AU - Weed, Michael R.
N1 - Funding Information:
The authors declare no conflict of interest. In the past 3 years, the authors have received compensation for professional services as follows: Dr Ator’s work has been funded by the NIH and she has received funding from Helsinn Healthcare to conduct an abuse liability evaluation of an unrelated compound. She has received compensation for consulting on abuse liability evaluation from Bristol Myers Squibb and F Hoffmann LaRoche. Dr Riddle’s, Dr Wilcox’s, and Dr Zhou’s work has been funded by the NIH. Dr Soto’s work has been funded by the NIH; he has received compensation, unrelated to his scientific work, for database/software consulting from Shands Hospital at the University of Florida. Dr Weed has been an employee of Bristol Myers Squibb since the end of the PET scans that occurred following the 18 months of treatment in this study. Bristol Myers-Squibb provided no financial support for these studies and had no scientific involvement. Dr Wong’s work has been funded by the NIH, Avid, Biotie, GE, Intracellular, Johnson & Johnson, Eli Lilly, H Lundbeck, Merck, Orexigen, Otsuka, F Hoffmann LaRoche, and Sanofi-Aventis. He has received compensation for consulting from Amgen.
Funding Information:
We thank Virginia Bogdan, Stacey Perry, Danielle Pyle, and Raymond Smith for expert technical assistance throughout the project, and Lani Swarthout for assistance with PET scans. We thank Rex Denton for thoughtful discussions on the cytogenetic data. We also wish to express gratitude to our NIMH program officers for the many ways in which they provided invaluable support and important contributions to research design and discussion of emerging data in the course of this Cooperative Agreement (U01)-supported project. This work was financially supported by National Institute on Mental Health grant U01-MH075378.
PY - 2012/11
Y1 - 2012/11
N2 - 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. 11 CMPH and 11 Craclopride dynamic PET scans were performed to image dopamine transporter and D 2 -like receptors, respectively. Binding potential (BP ND), an index of tracer-specific binding, and amphetamine-induced changes in BP ND of 11 Craclopride 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 D 2 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.
AB - 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. 11 CMPH and 11 Craclopride dynamic PET scans were performed to image dopamine transporter and D 2 -like receptors, respectively. Binding potential (BP ND), an index of tracer-specific binding, and amphetamine-induced changes in BP ND of 11 Craclopride 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 D 2 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.
KW - ADHD
KW - CANTAB
KW - PET
KW - amphetamine
KW - methylphenidate
KW - monkey
UR - http://www.scopus.com/inward/record.url?scp=84867581296&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84867581296&partnerID=8YFLogxK
U2 - 10.1038/npp.2012.119
DO - 10.1038/npp.2012.119
M3 - Article
C2 - 22805599
AN - SCOPUS:84867581296
VL - 37
SP - 2566
EP - 2579
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
SN - 0893-133X
IS - 12
ER -