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Neonatal domoic acid alters in vivo binding of [11C]yohimbine to α2-adrenoceptors in adult rat brain

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Abstract

Rationale

Epilepsy is a debilitating seizure disorder that affects approximately 50 million people. Noradrenaline reduces neuronal excitability, has anticonvulsant effects and is protective against seizure onset.

Objective

We investigated the role of α2-adrenoceptors in vivo in a neonatal domoic acid (DOM) rat model of epilepsy.

Methods

We injected male Sprague-Dawley rats daily from postnatal day 8–14 with saline or one of two sub-convulsive doses, 20 μg/kg (DOM20) or 60 μg/kg (DOM60) DOM, an AMPA/kainate receptor agonist. The rats were observed in open field, social interaction and forced swim tests at day 50, 75 and 98, respectively. At ~120 days of age, four rats per group were injected and scanned with [11C]yohimbine, an α2-adrenoceptor antagonist, and scanned in a Mediso micro positron emission tomography (PET) scanner to measure α2−adrenoceptor binding.

Results

DOM60-treated rats spent more time in the periphery during the open field test and had a significant 26–33 % reduction in [11C]yohimbine binding in the hypothalamus, hippocampus and orbital prefrontal cortex compared to saline-treated rats. On the other hand, DOM20 rats had a significant 34–40 % increase in [11C]yohimbine binding in the hypothalamus, amygdala and entorhinal cortex compared to saline-treated rats, with no obvious behavioural differences.

Conclusions

The current data clearly indicate that low concentrations of DOM given to rats in their second week of life induces long-term changes in α2-adrenoceptor binding in rat brain that may have relevance to the progression of an epilepsy phenotype.

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Acknowledgments

The authors thank the staff at the PET Centre and Translational Neuropsychiatric Unit at Aarhus University and Hospital. Special thanks to Jenny-Ann Phan for help with the free fraction method and Kim Vang for help with image analysis.

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Authors and Affiliations

  1. Department of Nuclear Medicine and PET Center, Aarhus University and Hospital, Aarhus, Denmark

    Majken B. Thomsen, Thea P. Lillethorup, Steen Jakobsen, Erik H. Nielsen, Mette Simonsen & Anne M. Landau

  2. Translational Neuropsychiatry Unit, Aarhus University, Risskov, Denmark

    Gregers Wegener, Anne M. Landau & R. Andrew Tasker

  3. Department of Biomedical Sciences, University of PEI, Charlottetown, Canada

    R. Andrew Tasker

Authors
  1. Majken B. Thomsen
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  2. Thea P. Lillethorup
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  3. Steen Jakobsen
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  4. Erik H. Nielsen
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  5. Mette Simonsen
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  6. Gregers Wegener
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  7. Anne M. Landau
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  8. R. Andrew Tasker
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Corresponding author

Correspondence to Anne M. Landau.

Ethics declarations

All animal procedures were approved by the Danish Committee on Ethics in Animal Experimentation.

Conflict of interest

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The authors declare that they have no conflict of interest.

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Funding

This study was supported by the Lundbeck Foundation grant number 2013–14,933 to G.W and R.A.T. and the Aarhus PET Centre.

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Thomsen, M.B., Lillethorup, T.P., Jakobsen, S. et al. Neonatal domoic acid alters in vivo binding of [11C]yohimbine to α2-adrenoceptors in adult rat brain. Psychopharmacology 233, 3779–3785 (2016). https://doi.org/10.1007/s00213-016-4416-5

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  • DOI: https://doi.org/10.1007/s00213-016-4416-5

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