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Aberrant glutamate signaling in the prefrontal cortex and striatum of the spontaneously hypertensive rat model of attention-deficit/hyperactivity disorder

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Abstract

Rationale

Attention-deficit/hyperactivity disorder (ADHD) is thought to involve hypofunctional catecholamine systems in the striatum, nucleus accumbens, and prefrontal cortex (PFC); however, recent clinical evidence has implicated glutamate dysfunction in the pathophysiology of ADHD. Recent studies show that increased stimulation of dopamine D2 and D4 receptors causes inhibition of N-methyl-d-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, respectively. The spontaneously hypertensive rat (SHR) model of ADHD combined type (C) has been found to have a hypofunctional dopamine system in the ventral striatum, nucleus accumbens, and PFC compared to the control Wistar Kyoto (WKY) strain.

Objectives

Based on the current understanding of typical dopamine–glutamate interactions, we hypothesized that the SHR model of ADHD would have a hyperfunctional glutamate system terminating in the striatum, nucleus accumbens, and PFC.

Results

High-speed amperometric recordings combined with four-channel microelectrode arrays to directly measure glutamate dynamics showed increased evoked glutamate release in the PFC (cingulate and infralimbic cortices, p < 0.05) and also in the striatum (p < 0.05) of the SHR (ADHD-C) as compared to the WKY. Finally, glutamate uptake was discovered to be aberrant in the PFC, but not the striatum, of the SHR when compared to the control WKY strain.

Conclusions

These results suggest that the glutamatergic system in the PFC of the SHR model of ADHD is hyperfunctional and that targeting glutamate in the PFC could lead to the development of novel therapeutics for the treatment of ADHD.

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Acknowledgments

The authors would like to thank Alexander Saunders for his help with cryosectioning and staining the tissue. These experiments comply with the current laws of the USA.

This study was supported by USPHS grant 5T32AG000242-13 and DARPA N66001-09-C-2080. The project described was also supported by the National Center for Advancing Translational Sciences, UL1TR000117. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Conflict of interest

The authors disclose that Greg A. Gerhardt is the owner of Quanteon Limited Liability Company (Nicholasville, KY). Quanteon developed the FAST system utilized for these studies. No financial support was provided on behalf of Quanteon. The authors, therefore, declare no competing financial interests. All authors have full control of the primary data and thus agree to allow the journal to review data if requested.

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Authors and Affiliations

  1. Department of Anatomy and Neurobiology, University of Kentucky Chandler Medical Center, Lexington, KY, 40536, USA

    Erin M. Miller, Francois Pomerleau, Peter Huettl, Greg A. Gerhardt & Paul E. A. Glaser

  2. Department of Pediatrics, University of Kentucky Chandler Medical Center, Lexington, KY, 40536, USA

    Paul E. A. Glaser

  3. Department of Psychiatry, University of Kentucky Chandler Medical Center, Lexington, KY, 40536, USA

    Greg A. Gerhardt & Paul E. A. Glaser

  4. Department of Neurology, University of Kentucky Chandler Medical Center, Lexington, KY, 40536, USA

    Greg A. Gerhardt

  5. Center for Microelectrode Technology, University of Kentucky Chandler Medical Center, Lexington, KY, 40536, USA

    Erin M. Miller, Francois Pomerleau, Peter Huettl, Greg A. Gerhardt & Paul E. A. Glaser

  6. Parkinson’s Disease Translational Research Center of Excellence, University of Kentucky Chandler Medical Center, Lexington, KY, 40536, USA

    Erin M. Miller, Francois Pomerleau, Peter Huettl, Greg A. Gerhardt & Paul E. A. Glaser

  7. University of Kentucky, MN 206 Medical Sciences Bldg., 800 Rose Street, Lexington, KY, 40536-0298, USA

    Paul E. A. Glaser

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  1. Erin M. Miller
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Correspondence to Paul E. A. Glaser.

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Miller, E.M., Pomerleau, F., Huettl, P. et al. Aberrant glutamate signaling in the prefrontal cortex and striatum of the spontaneously hypertensive rat model of attention-deficit/hyperactivity disorder. Psychopharmacology 231, 3019–3029 (2014). https://doi.org/10.1007/s00213-014-3479-4

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