The Journal of Neuroscience, July 4, 2007
Methylphenidate Administration to Juvenile Rats Alters Brain Areas Involved in Cognition, Motivated Behaviors, Appetite, and Stress.
Jason D. Gray, 1 Michael Punsoni, 1 Nora E. Tabori, 1 ,3 Jay T. Melton, 1 Victoria Fanslow, 1 Mary J. Ward, 2 Bojana Zupan, 1 David Menzer,1 Jackson Rice, 1 Carrie T. Drake, 1 Russell D. Romeo, 3 Wayne G. Brake, 4 Annelyn Torres-Reveron, 1 and Teresa A. Milner 1 ,3
1 Division of Neurobiology, Department of Neurology and Neuroscience and 2 Department of Pediatrics, Weill-Cornell Medical College, New York, New York 10021, 3 Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, New York 10021, and 4 Centre for Studies in Behavioral Neurobiology, Department of Psychology, Concordia University, Montreal, Canada H4B 1R6
Correspondence should be addressed to Dr. Teresa A. Milner, Division of Neurobiology, Weill-Cornell Medical College, 411 East 69th Street, New York, NY 10021. Email: tmilner@mail.med.cornell.edu
Thousands of children receive methylphenidate (MPH; Ritalin) for attention deficit/hyperactivity disorder (ADHD), yet the long-term neurochemical consequences of MPH treatment are unknown. To mimic clinical Ritalin treatment in children, male rats were injected with MPH (5 mg/kg) or vehicle twice daily from postnatal day 7 (PND7)–PND35. At the end of administration (PND35) or in adulthood (PND135), brain sections from littermate pairs were immunocytochemically labeled for neurotransmitters and cytological markers in 16 regions implicated in MPH effects and/or ADHD etiology. At PND35, the medial prefrontal cortex (mPFC) of rats given MPH showed 55% greater immunoreactivity (-ir) for the catecholamine marker tyrosine hydroxylase (TH), 60% more Nissl-stained cells, and 40% less norepinephrine transporter (NET)-ir density. In hippocampal dentate gyrus, MPH-receiving rats showed a 51% decrease in NET-ir density and a 61% expanded distribution of the new-cell marker PSA-NCAM (polysialylated form of neural cell adhesion molecule). In medial striatum, TH-ir decreased by 21%, and in hypothalamus neuropeptide Y-ir increased by 10% in MPH-exposed rats. At PND135, MPH-exposed rats exhibited decreased anxiety in the elevated plus-maze and a trend for decreased TH-ir in the mPFC. Neither PND35 nor PND135 rats showed major structural differences with MPH exposure. These findings suggest that developmental exposure to high therapeutic doses of MPH has short-term effects on select neurotransmitters in brain regions involved in motivated behaviors, cognition, appetite, and stress. Although the observed neuroanatomical changes largely resolve with time, chronic modulation of young brains with MPH may exert effects on brain neurochemistry that modify some behaviors even in adulthood.