Chronic methylphenidate treatment enhances striatal dopamine neurotransmission after experimental traumatic brain injury.
Traumatic brain injury (TBI) results in functional deficits that often are effectively treated clinically with the neurostimulant, methylphenidate (MPH). We hypothesized that daily MPH administration would reverse striatal neurotransmission deficits observed in the controlled cortical impact (CCI) model of TBI. CCI or naïve rats received daily injections of MPH (5 mg/kg) or saline for 14 days and were assessed on day 15 using fast scan cyclic voltammetry. Dopamine (DA) transporter (DAT) localization, DA-related proteins, and transcription factor (c-fos) expression were also assessed. CCI resulted in reduced electrically evoked overflow of DA and maximal velocity of DA clearance (V(max)). In contrast, CCI was associated with a decrease in the apparent K(M) of DAT. Daily dose of MPH after CCI resulted in robust increases in evoked DA overflow and V(max) as well as increased apparent K(M). Reductions in total striatal DAT expression occurred after CCI and were not further affected by MPH. In contrast, membrane-bound striatal DAT levels were increased in both CCI groups. MPH post-CCI significantly increased striatal c-fos levels compared with saline. These results support the hypothesis that daily MPH improves striatal DA neurotransmission after CCI. DAT expression and transcriptional changes affecting DA protein function may underlie the injury and MPH-induced alterations in neurotransmission observed.
Wagner
Amy K
AK
Department of Physical Medicine and Rehabilitation, University of Pittsburgh School of Medicine, Pennsylvania, USA. Wagnerak@upmc.edu
Drewencki
Laura L
LL
Chen
Xiangbai
X
Santos
F Ryan
FR
Khan
Amina S
AS
Harun
Rashed
R
Torres
Gonzalo E
GE
Michael
Adrian C
AC
Dixon
C Edward
CE
D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000697:Central Nervous System Stimulants / Q000494:pharmacology / Q000627:therapeutic use; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004334:Drug Administration Schedule; D007700:Kinetics; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology* / Q000627:therapeutic use; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D008774:Methylphenidate; D004298:Dopamine