Short-term effects of adolescent methylphenidate exposure on brain striatal gene expression and sexual/endocrine parameters in male rats.
Exposure to methylphenidate (MPH) during adolescence is the elective therapy for attention deficit/hyperactivity disorder (ADHD) children, but raises major concerns for public health, due to possibly persistent neurobehavioral changes. Rats (30- to 44-days old) were administered MPH (2 mg/kg, i.p once daily) or saline (SAL). At the end of the treatment we collected plasma, testicular, liver, and brain (striatum) samples. The testes and liver were used to evaluate conventional reproductive and metabolic endpoints. Testes of MPH-exposed rats weighed more and contained an increased quantity of sperm, whereas testicular levels of testosterone (TST) were markedly decreased. The MPH treatment exerted an inductive effect on enzymatic activity of TST hydroxylases, resulting in increased hepatic TST catabolism. These findings suggest that subchronic MPH exposure in adolescent rats could have a trophic action on testis growth and a negative impact on TST metabolism. We have analyzed striatal gene expression profiles as a consequence of MPH exposure during adolescence, using microarray technology. More than 700 genes were upregulated in the striatum of MPH-treated rats (foldchange >1.5). A first group of genes were apparently involved in migration of immature neural/glial cells and/or growth of novel axons. These genes include matrix proteases (ADAM-1, MMP14), their inhibitors (TIMP-2, TIMP-3), the hyaluronan-mediated motility receptor (RHAMM), and growth factors (transforming growth factor-beta3 [TGF-beta3] and fibroblast growth factor 14 [FGF14]). A second group of genes were suggestive of active axonal myelination. These genes mediate survival of immature cells after contact with newly produced axonal matrix (laminin B1, collagens, integrin alpha 6) and stabilization of myelinating glia-axon contacts (RAB13, contactins 3 and 4). A third group indicated the appearance and/or upregulation of mature processes. The latter included genes for: K+ channels (TASK-1, TASK-5), intercellular junctions (connexin30), neurotransmitter receptors (adrenergic alpha 1B, kainate 2, serotonin 7, GABA-A), as well as major proteins responsible for their transport and/or anchoring (Homer 1, MAGUK MPP3, Shank2). All these genes were possibly involved in synaptic plasticity, namely the formation, maturation, and stabilization of new neural connections within the striatum. MPH treatment seems to potentiate synaptic plasticity, which is an age-dependent developmental phenomenon that adolescent rats are very likely to show, compared to adults. Our observations suggest that adolescent MPH exposure causes only transient changes in reproductive and hormonal parameters, and a more enduring enhancement of neurobehavioral plasticity.
Adriani
Walter
W
Department of Cell Biology & Neurosciences, Behavioural Neuroscience Section, Istituto Superiore di Sanità, viale Regina Elena 299, I-00161 Roma, Italy. adriani@iss.it
Leo
Damiana
D
Guarino
Maria
M
Natoli
Alessia
A
Di Consiglio
Emma
E
De Angelis
Giovanna
G
Traina
Elsa
E
Testai
Emanuela
E
Perrone-Capano
Carla
C
Laviola
Giovanni
G
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002465:Cell Movement; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D003713:Dendritic Cells / Q000502:physiology; D015259:Dopamine Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D020869:Gene Expression Profiling; D008099:Liver / Q000378:metabolism* / Q000502:physiology; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology*; D008954:Models, Biological; D009413:Nerve Fibers, Myelinated / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D051381:Rats; D015398:Signal Transduction; D013737:Testis / Q000378:metabolism* / Q000502:physiology
D015259:Dopamine Agents; D008774:Methylphenidate