title: Effect of methylphenidate treatment during adolescence on norepinephrine transporter function in orbitofrontal cortex in a rat model of attention deficit hyperactivity disorder.
abstract: Attention deficit hyperactivity disorder (ADHD) is associated with hypofunctional medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC). Methylphenidate (MPH) remediates ADHD, in part, by inhibiting the norepinephrine transporter (NET). MPH also reduces ADHD-like symptoms in spontaneously hypertensive rats (SHRs), a model of ADHD. However, effects of chronic MPH treatment on NET function in mPFC and OFC in SHR have not been reported. In the current study, long-term effects of repeated treatment with a therapeutically relevant oral dose of MPH during adolescence on NET function in subregions of mPFC (cingulate gyrus, prelimbic cortex and infralimbic cortex) and in the OFC of adult SHR, Wistar-Kyoto (WKY, inbred control) and Wistar (WIS, outbred control) rats were determined using in vivo voltammetry. Following local ejection of norepinephrine (NE), uptake rate was determined as peak amplitude (Amax)× first-order rate constant (k-1). In mPFC subregions, no strain or treatment effects were found in NE uptake rate. In OFC, NE uptake rate in vehicle-treated adult SHR was greater than in adult WKY and WIS administered vehicle. MPH treatment during adolescence normalized NE uptake rate in OFC in SHR. Thus, the current study implicates increased NET function in OFC as an underlying mechanism for reduced noradrenergic transmission in OFC, and consequently, the behavioral deficits associated with ADHD. MPH treatment during adolescence normalized NET function in OFC in adulthood, suggesting that the therapeutic action of MPH persists long after treatment cessation and may contribute to lasting reductions in deficits associated with ADHD.
authors: Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY 40536, USA.
authors: Sucharita S
authors: SS
authors: Somkuwar
authors: Department of Psychological and Brain Sciences, Boston University, Boston, MA 02215, USA.
authors: Kathleen M
authors: KM
authors: Kantak
authors: Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY 40536, USA. Electronic address: ldwoskin@email.uky.edu.
authors: Linda P
authors: LP
authors: Dwoskin
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000473:pathology; D000697:Central Nervous System Stimulants / Q000627:therapeutic use*; D003214:Conditioning, Classical / Q000187:drug effects; D004195:Disease Models, Animal; D004563:Electrochemistry; D005260:Female; D008297:Male; D008774:Methylphenidate / Q000627:therapeutic use*; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D010879:Piperazines / Q000627:therapeutic use; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
chemical_list: C461261:(1-(2-(bis(4-fluorophenyl)methoxy)ethyl)-4-(3-hydroxy-3-phenylpropyl) piperazinyl decanoate); D000697:Central Nervous System Stimulants; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010879:Piperazines; D008774:Methylphenidate; D009638:Norepinephrine
keywords: Attention deficit/hyperactivity disorder; In vivo voltammetry; Norepinephrine transporter; Orbitofrontal cortex; Spontaneously hypertensive rat