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Ketamine-induced brain activation in awake female nonhuman primates: a translational functional imaging model

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Abstract

Rationale

There is significant interest in the NMDA receptor antagonist ketamine due to its efficacy in treating depressive disorders and its induction of psychotic-like symptoms that make it a useful tool for modeling psychosis.

Objective

The present study extends the successful development of an apparatus and methodology to conduct pharmacological MRI studies in awake rhesus monkeys in order to evaluate the CNS effects of ketamine.

Methods

Functional MRI scans were conducted in four awake adult female rhesus monkeys during sub-anesthetic intravenous (i.v.) infusions of ketamine (0.345 mg/kg bolus followed by 0.256 mg/kg/h constant infusion) with and without risperidone pretreatment (0.06 mg/kg). Statistical parametric maps of ketamine-induced blood oxygenation level–dependent (BOLD) activation were obtained with appropriate general linear regression models (GLMs) incorporating motion and hemodynamics of ketamine infusion.

Results

Ketamine infusion induced and sustained robust BOLD activation in a number of cortical and subcortical regions, including the thalamus, cingulate gyrus, and supplementary motor area. Pretreatment with the antipsychotic drug risperidone markedly blunted ketamine-induced activation in many brain areas.

Conclusions

The results are remarkably similar to human imaging studies showing ketamine-induced BOLD activation in many of the same brain areas, and pretreatment with risperidone or another antipsychotic blunting the ketamine response to a similar extent. The strong concordance of the functional imaging data in humans with these results from nonhuman primates highlights the translational value of the model and provides an excellent avenue for future research examining the CNS effects of ketamine. This model may also be a useful tool for evaluating the efficacy of novel antipsychotic drugs.

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Acknowledgments

The authors declare no competing financial interests. This research was supported by P51OD11132 (Yerkes National Primate Research Center), Sunovion Pharmaceutical, Ltd. (LLH) and DA031246 (LLH). Special thanks to the Yerkes Imaging Center, technicians Marisa Olsen and Juliet Brown, and to Christopher Muly, MD, PhD.

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    Authors and Affiliations

    1. Yerkes National Primate Research Center, Emory University, 954 Gatewood Rd NE, Atlanta, GA, 30329, USA

      Eric Maltbie, Naoko Urushino, Doty Kempf & Leonard Howell

    2. Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA, USA

      Kaundinya Gopinath

    3. Dainippon Sumitomo Pharma, Co. Ltd., Osaka, Japan

      Naoko Urushino

    4. Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA

      Leonard Howell

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    1. Eric Maltbie
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    2. Kaundinya Gopinath
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    5. Leonard Howell
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    Corresponding author

    Correspondence to Leonard Howell.

    Additional information

    Eric Maltbie and Kaundinya Gopinath contributed equally to this work.

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    Maltbie, E., Gopinath, K., Urushino, N. et al. Ketamine-induced brain activation in awake female nonhuman primates: a translational functional imaging model. Psychopharmacology 233, 961–972 (2016). https://doi.org/10.1007/s00213-015-4175-8

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    • DOI: https://doi.org/10.1007/s00213-015-4175-8

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