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.

Keywords: Attention deficit/hyperactivity disorder; In vivo voltammetry; Norepinephrine transporter; Orbitofrontal cortex; Spontaneously hypertensive rat.

Fig 1

Neuroanatomical localization of electrodes. The regions of interest for evaluating NET function were lateral orbitofrontal cortex (LO; Top panel), the cingulate gyrus (CG), dorsal and ventral prelimbic cortex (PrL), and infralimbic cortex (IL; Bottom panel). Placements of the carbon-fiber electrode tips in the rodent LO (Top panel) and IL (Bottom panel) are shown for experiments determining the effect of dopamine transporter (DAT) inhibition (x marks) as well as for the experiments evaluating the effect of adolescent treatment with MPH (black dots).

Fig 2

First order uptake rate of norepinephrine (NE) in the lateral orbitofrontal cortex (LO) of adult Spontaneously Hypertensive Rat (SHR), Wistar-Kyoto (WKY) and Wistar (WIS) rats treated with methylphenidate (MPH) or vehicle (VEH) during adolescence. NE (100 μM; with GBR 12909, 50 nM) was applied locally to LO of each rat. First order uptake rate (in nM/sec) was mean ± S.E.M. product of the maximum amplitude (A_max) of the NE signal and the first order fitting of the signal decay (k_-1). n = 8–9/group; * p < 0.05 compared to the respective VEH control; ^# p < 0.05 compared to VEH-treated WKY and WIS.