title: Prefrontal cortical and striatal transcriptional responses to the reinforcing effect of repeated methylphenidate treatment in the spontaneously hypertensive rat, animal model of attention-deficit/hyperactivity disorder (ADHD).
abstract: BACKGROUND
  Methylphenidate is the most commonly used stimulant drug for the treatment of attention-deficit/hyperactivity disorder (ADHD). Research has found that methylphenidate is a "reinforcer" and that individuals with ADHD also abuse this medication. Nevertheless, the molecular consequences of long-term recreational methylphenidate use or abuse in individuals with ADHD are not yet fully known.
  
  
  METHODS
  Spontaneously hypertensive rats (SHR), the most validated and widely used ADHD animal model, were pretreated with methylphenidate (5 mg/kg, i.p.) during their adolescence (post-natal day [PND] 42-48) and tested for subsequent methylphenidate-induced conditioned place preference (CPP) and self-administration. Thereafter, the differentially expressed genes in the prefrontal cortex (PFC) and striatum of representative methylphenidate-treated SHRs, which showed CPP to and self-administration of methylphenidate, were analyzed.
  
  
  RESULTS
  Genome-wide transcriptome profiling analyses revealed 30 differentially expressed genes in the PFC, which include transcripts involved in apoptosis (e.g. S100a9, Angptl4, Nfkbia), transcription (Cebpb, Per3), and neuronal plasticity (Homer1, Jam2, Asap1). In contrast, 306 genes were differentially expressed in the striatum and among them, 252 were downregulated. The main functional categories overrepresented among the downregulated genes include those involved in cell adhesion (e.g. Pcdh10, Ctbbd1, Itgb6), positive regulation of apoptosis (Perp, Taf1, Api5), (Notch3, Nsbp1, Sik1), mitochondrion organization (Prps18c, Letm1, Uqcrc2), and ubiquitin-mediated proteolysis (Nedd4, Usp27x, Ube2d2).
  
  
  CONCLUSIONS
  Together, these changes indicate methylphenidate-induced neurotoxicity, altered synaptic and neuronal plasticity, energy metabolism and ubiquitin-dependent protein degradation in the brains of methylphenidate-treated SHRs, which showed methylphenidate CPP and self-administration. In addition, these findings may also reflect cognitive impairment associated with chronic methylphenidate use as demonstrated in preclinical studies. Future studies are warranted to determine the clinical significance of the present findings with regard to long-term recreational methylphenidate use or abuse in individuals with ADHD.
authors.forename: Ike
authors.initials: I
authors.lastname: dela Peña
authors.forename: Hee Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Aeree
authors.initials: A
authors.lastname: Sohn
authors.forename: Bung-Nyun
authors.initials: BN
authors.lastname: Kim
authors.forename: Doug Hyun
authors.initials: DH
authors.lastname: Han
authors.forename: Jong Hoon
authors.initials: JH
authors.lastname: Ryu
authors.forename: Chan Young
authors.initials: CY
authors.lastname: Shin
authors.affiliation: Uimyung Research Institute for Neuroscience, Sahmyook University, 26-21 Kongreung-2-dong, Hwarangro- 815 Nowon-gu, Seoul 139-742, Korea. minsoonoh@snu.ac.kr.
authors.forename: Minsoo
authors.initials: M
authors.lastname: Noh
authors.forename: Jae Hoon
authors.initials: JH
authors.lastname: Cheong
mesh_terms: D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000008:administration & dosage* / Q000627:therapeutic use; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D008774:Methylphenidate / Q000008:administration & dosage* / Q000627:therapeutic use; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D012054:Reinforcement, Psychology; D012646:Self Administration
chemical_list: D000697:Central Nervous System Stimulants; D008774:Methylphenidate