Effect of methylphenidate treatment during adolescence on norepinephrine transporter function in orbitofrontal cortex in a rat model of attention deficit hyperactivity disorder

Sucharita S. Somkuwar; Kathleen M. Kantak; Linda P. Dwoskin

doi:10.1016/j.jneumeth.2015.02.002

Effect of methylphenidate treatment during adolescence on norepinephrine transporter function in orbitofrontal cortex in a rat model of attention deficit hyperactivity disorder

Sucharita S. Somkuwar
, Kathleen M. Kantak
, Linda P. Dwoskin

Producción científica: Article › revisión exhaustiva

20 Citas (Scopus)

Resumen

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 (A_max)×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.

Idioma original	English
Páginas (desde-hasta)	55-63
Número de páginas	9
Publicación	Journal of Neuroscience Methods
Volumen	252
DOI	https://doi.org/10.1016/j.jneumeth.2015.02.002
Estado	Published - jun 13 2015

Nota bibliográfica

Publisher Copyright:
© 2015 Elsevier B.V..

Financiación

This study was funded by National Institute of Health or NIHg rant R01 DA11716, P50 DA05312, UL1 TR000117 and a Kentucky Opportunity Fellowship, USA. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse. Experiments adhered to the Institutional Animal Care and Use Committee guidelines for animal research. This study was funded by National Institute of Health or NIH grant R01 DA11716 , P50 DA05312 , UL1 TR000117 and a Kentucky Opportunity Fellowship , USA. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse. Experiments adhered to the Institutional Animal Care and Use Committee guidelines for animal research.

Financiadores	Número del financiador
National Institutes of Health (NIH)	R01 DA11716, P50DA005312
National Institutes of Health (NIH)
National Center for Advancing Translational Sciences (NCATS)	UL1TR000117
National Center for Advancing Translational Sciences (NCATS)

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.jneumeth.2015.02.002

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@article{9c718d1f68b44b3ba45b8bd3f0179a19,

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.",

keywords = "Attention deficit/hyperactivity disorder, In vivo voltammetry, Norepinephrine transporter, Orbitofrontal cortex, Spontaneously hypertensive rat",

author = "Somkuwar, \{Sucharita S.\} and Kantak, \{Kathleen M.\} and Dwoskin, \{Linda P.\}",

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AU - Somkuwar, Sucharita S.

AU - Kantak, Kathleen M.

AU - Dwoskin, Linda P.

PY - 2015/6/13

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N2 - 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.

AB - 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.

KW - Attention deficit/hyperactivity disorder

KW - In vivo voltammetry

KW - Norepinephrine transporter

KW - Orbitofrontal cortex

KW - Spontaneously hypertensive rat

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M3 - Article

C2 - 25680322

AN - SCOPUS:84952629819

SN - 0165-0270

VL - 252

SP - 55

EP - 63

JO - Journal of Neuroscience Methods

JF - Journal of Neuroscience Methods

ER -

Effect of methylphenidate treatment during adolescence on norepinephrine transporter function in orbitofrontal cortex in a rat model of attention deficit hyperactivity disorder

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