Somkuwar Sucharita S, Kantak Kathleen M, Dwoskin Linda P
Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY 40536, USA.
Department of Psychological and Brain Sciences, Boston University, Boston, MA 02215, USA.
J Neurosci Methods. 2015 Aug 30;252:55-63. doi: 10.1016/j.jneumeth.2015.02.002. Epub 2015 Feb 11.
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.
注意缺陷多动障碍（ADHD）与内侧前额叶皮质（mPFC）和眶额皮质（OFC）功能低下有关。哌甲酯（MPH）通过抑制去甲肾上腺素转运体（NET）部分改善ADHD。MPH还可减轻自发性高血压大鼠（SHR，一种ADHD模型）的ADHD样症状。然而，尚未有关于慢性MPH治疗对SHR的mPFC和OFC中NET功能影响的报道。在本研究中，使用体内伏安法测定了青春期给予治疗相关口服剂量的MPH对成年SHR、Wistar-Kyoto（WKY，近交系对照）和Wistar（WIS，远交系对照）大鼠的mPFC亚区（扣带回、前额叶皮质和边缘下皮质）和OFC中NET功能的长期影响。在局部注射去甲肾上腺素（NE）后，摄取率被确定为峰值幅度（Amax）×一级速率常数（k-1）。在mPFC亚区，未发现NE摄取率的品系或治疗效应。在OFC中，给予载体的成年SHR的NE摄取率高于给予载体的成年WKY和WIS。青春期MPH治疗使SHR的OFC中NE摄取率正常化。因此，本研究表明OFC中NET功能增加是OFC中去甲肾上腺素能传递减少的潜在机制，进而也是与ADHD相关的行为缺陷的潜在机制。青春期MPH治疗使成年期OFC中的NET功能正常化，这表明MPH的治疗作用在治疗停止后很长时间仍持续存在，可能有助于持久减少与ADHD相关的缺陷。
