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Methylphenidate administration to adolescent rats determines plastic changes on reward-related behavior and striatal gene expression
被引:94
作者:
Adriani, Walter
Leo, Damiana
Greco, Dario
Rea, Monica
di Porzio, Umberto
Laviola, Giovanni
Perrone-Capano, Carla
机构:
[1] CNR, Inst Genet & Biophys A Buzzati Traverso, I-80131 Naples, Italy
[2] Ist Super Sanita, Behav Neurosci Sect, Dept Cell Biol & Neurosci, I-00161 Rome, Italy
[3] Univ Helsinki, Inst Biotechnol, Helsinki, Finland
[4] Univ Catanzaro Magna Graecia, Dept Pharmacobiol, Roccelletta Di Borgia, CZ, Italy
关键词:
ADHD;
dopamine;
flexibility;
gene expression profiling;
habit;
PSD family;
D O I:
10.1038/sj.npp.1300962
中图分类号:
Q189 [神经科学];
学科分类号:
071006 ;
摘要:
Administration of methylphenidate (MPH, Ritalin (R)) to children with attention deficit hyperactivity disorder (ADHD) is an electivetherapy, 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 alpha 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.
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页码:1946 / 1956
页数:11
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