PMID- 17156936
OWN - NLM
STAT- MEDLINE
DCOM- 20070411
LR  - 20131121
IS  - 0306-4522 (Print)
IS  - 0306-4522 (Linking)
VI  - 144
IP  - 3
DP  - 2007 Feb 9
TI  - Methylphenidate regulates activity regulated cytoskeletal associated but not 
      brain-derived neurotrophic factor gene expression in the developing rat striatum.
PG  - 969-84
AB  - Methylphenidate (MPH) is a psychostimulant drug used to treat attention deficit 
      hyperactivity disorder in children. To explore the central effects of chronic 
      MPH, we investigated the expression of an effector immediate early gene, activity 
      regulated cytoskeletal associated (arc), and the neurotrophin, brain-derived 
      neurotrophic factor (bdnf) in the brain of immature and adult rats following 
      repeated MPH. Prepubertal (postnatal day (PD) 25-38) and adult (PD 53-66) male 
      rats were injected once daily for: a) 14 days with saline or MPH (2 or 10 mg/kg; 
      s.c.) or b) 13 days with saline followed by a single dose of MPH (2 or 10 mg/kg; 
      s.c.). To determine possible long-term effects of MPH, prepubertal rats were 
      allowed a drug-free period of 4 weeks following the 14 days of treatment, and 
      then were given a challenge dose of MPH. We demonstrated, for the first time, 
      that an acute injection of MPH increased levels of activity-regulated 
      cytoskeletal protein (ARC) and arc mRNA in the prepubertal rat striatum and 
      cingulate/frontal cortex. This response was significantly attenuated by chronic 
      MPH. The desensitization in arc expression observed in prepubertal rats persisted 
      in the adult striatum following a later MPH challenge. In contrast to these data 
      we observed little effect of MPH on bdnf expression. We also developed an 
      effective, non-stressful technique to treat freely moving immature rats with oral 
      MPH. Consistent with the results described above, we observed that oral MPH (7.5 
      and 10 mg/kg) also increased arc expression in the prepubertal rat striatum. 
      However, unlike the effects of injected MPH, repeated oral MPH (7.5 mg/kg) did 
      not alter the normal arc response. This result raises the important possibility 
      that oral doses of MPH that reproduce clinically relevant blood levels of MPH may 
      not down-regulate gene expression, at least in the short term (14 days). We 
      confirmed, using mass spectrometry, that the oral doses of MPH used in our 
      experiments yielded blood levels within the clinical range observed in children. 
      The novel oral administration paradigm that we describe thus provides a 
      clinically relevant animal model to further explore the effects of chronic drug 
      exposure on central gene expression in the developing rat brain.
FAU - Chase, T
AU  - Chase T
AD  - Department of Physiology and Biophysics, Faculty of Medicine, Dalhousie 
      University, College Street, Halifax, Nova Scotia, Canada B3H 1X5.
FAU - Carrey, N
AU  - Carrey N
FAU - Soo, E
AU  - Soo E
FAU - Wilkinson, M
AU  - Wilkinson M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20061206
PL  - United States
TA  - Neuroscience
JT  - Neuroscience
JID - 7605074
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Central Nervous System Stimulants)
RN  - 0 (Cytoskeletal Proteins)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (activity regulated cytoskeletal-associated protein)
RN  - 207ZZ9QZ49 (Methylphenidate)
SB  - IM
MH  - Administration, Oral
MH  - Aging/drug effects/physiology
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/*genetics
MH  - Central Nervous System Stimulants/pharmacology
MH  - Corpus Striatum/*drug effects/growth & development/*metabolism
MH  - Cytoskeletal Proteins/*genetics
MH  - Drug Administration Schedule
MH  - Gene Expression Regulation/*drug effects/physiology
MH  - Male
MH  - Methylphenidate/*pharmacology
MH  - Nerve Tissue Proteins/*genetics
MH  - Neurons/drug effects/metabolism
MH  - RNA, Messenger/drug effects/metabolism
MH  - Rats
MH  - Up-Regulation/drug effects/physiology
EDAT- 2006/12/13 09:00
MHDA- 2007/04/12 09:00
CRDT- 2006/12/13 09:00
PHST- 2006/05/09 00:00 [received]
PHST- 2006/09/28 00:00 [revised]
PHST- 2006/10/26 00:00 [accepted]
PHST- 2006/12/13 09:00 [pubmed]
PHST- 2007/04/12 09:00 [medline]
PHST- 2006/12/13 09:00 [entrez]
AID - S0306-4522(06)01429-1 [pii]
AID - 10.1016/j.neuroscience.2006.10.035 [doi]
PST - ppublish
SO  - Neuroscience. 2007 Feb 9;144(3):969-84. doi: 10.1016/j.neuroscience.2006.10.035. 
      Epub 2006 Dec 6.