1. ¹Department of Cell Biology & Neurosciences, Behavioral Neuroscience Section, Istituto Superiore di Sanità, Roma, Italy
2. ²Institute of Genetics and Biophysics 'A. Buzzati Traverso', CNR, Napoli, Italy
3. ³Institute of Biotechnology, University of Helsinki, Helsinki, Finland
4. ⁴Department of Pharmacobiology, University of Catanzaro 'Magna Graecia', Roccelletta di Borgia (CZ), Italy

Correspondence: Professor C Perrone-Capano, Institute of Genetics and Biophysics 'A. Buzzati Traverso', CNR, Via Pietro Castellino 111, Naples 80131, Italy. Tel: +390816132362; Fax: +390816132350; E-mail: perrone@igb.cnr.it

⁵Both authors have equally contributed to this work.

Received 7 July 2005; Revised 3 October 2005; Accepted 4 October 2005; Published online 23 November 2005.

Abstract

Administration of methylphenidate (MPH, Ritalin^®) to children with attention deficit hyperactivity disorder (ADHD) is an elective therapy, but raises concerns for public health, due to possible persistent neurobehavioral alterations. Wistar adolescent rats (30 to 46 day old) were administered MPH or saline (SAL) for 16 days, and tested for reward-related and motivational-choice behaviors. When tested in adulthood in a drug-free state, MPH-pretreated animals showed increased choice flexibility and economical efficiency, as well as a dissociation between dampened place conditioning and more marked locomotor sensitization induced by cocaine, compared to SAL-pretreated controls. The striatal complex, a core component of the natural reward system, was collected both at the end of the MPH treatment and in adulthood. Genome-wide expression profiling, followed by RT-PCR validation on independent samples, showed that three members of the postsynaptic-density family and five neurotransmitter receptors were upregulated in the adolescent striatum after subchronic MPH administration. Interestingly, only genes for the kainate 2 subunit of ionotropic glutamate receptor (Grik2, also known as KA2) and the 5-hydroxytryptamine (serotonin) receptor 7 (Htr7) (but not GABA_A subunits and adrenergic receptor 1b) were still upregulated in adulthood. cAMP responsive element-binding protein and Homer 1a transcripts were modulated only as a long-term effect. In summary, our data indicate short-term changes in neural plasticity, suggested by modulation of expression of key genes, and functional changes in striatal circuits. These modifications might in turn trigger enduring changes responsible for the adult neurobehavioral profile, that is, altered processing of incentive values and a modified flexibility/habit balance.