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Increased glutamate-stimulated release of dopamine in substantia nigra of a rat model for attention-deficit/hyperactivity disorder—lack of effect of methylphenidate

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Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a behavioural disorder that has been associated with dysfunction of the dopaminergic system. Abnormal dopamine function could be the result of a primary defect in dopamine neurons (neuronal firing, dopamine transporter, synthesis, receptor function) or an indirect result of impaired glutamate and/or noradrenergic regulation of dopamine neurons. There is considerable evidence to suggest that dopamine release is impaired at mesolimbic and nigrostriatal dopaminergic terminals. However, it is not known whether dysregulation occurs at the level of the cell bodies in the ventral tegmental area of the midbrain (VTA) and substantia nigra (SN). An in vitro superfusion technique was used to measure dopamine release in a widely used model of ADHD, the spontaneously hypertensive rat (SHR), and its normotensive Wistar-Kyoto (WKY) control. At approximately 30 days of age, rats were analysed for behavioural differences in the open field in response to acute treatment with methylphenidate (0.5 to 2 mg/kg in condensed milk, oral self-administration). In addition, rats were treated chronically with methylphenidate (2 mg/kg, oral self-administration, twice daily for 14 days from postnatal day 21 to 34) before the VTA and the SN were analysed for glutamate—stimulated and depolarization—evoked release of dopamine in these areas. In support of its use as an animal model for ADHD, SHR were more active in the open field and displayed less anxiety-like behaviour than WKY. Neither strain showed any effect of treatment with methylphenidate. A significant difference was observed in glutamate-stimulated release of dopamine in the SN of SHR and WKY, with SHR releasing more dopamine, consistent with the hypothesis of altered glutamate regulation of dopamine neurons in SHR.

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Acknowledgments

This work was supported by the South African Medical Research Council and the University of Cape Town. The authors would also like to thank Mr Letlogonolo Selaledi and Mrs Nuraan Ismail for assistance with animal care. Miss Fleur Warton was the recipient of a National Research Foundation scholarship.

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  1. Division of Physiology, Department of Human Biology, University of Cape Town, Observatory, Cape Town, 7925, South Africa

    Fleur L. Warton, Fleur M. Howells & Vivienne A. Russell

  2. Neuroscience Laboratory, University of Cape Town, Room 5.02, Anatomy Building, Anzio Road, Observatory, Cape Town, 7925, South Africa

    Vivienne A. Russell

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  1. Fleur L. Warton
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Warton, F.L., Howells, F.M. & Russell, V.A. Increased glutamate-stimulated release of dopamine in substantia nigra of a rat model for attention-deficit/hyperactivity disorder—lack of effect of methylphenidate. Metab Brain Dis 24, 599–613 (2009). https://doi.org/10.1007/s11011-009-9166-1

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