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Alprazolam-induced EEG spectral power changes in rhesus monkeys: a translational model for the evaluation of the behavioral effects of benzodiazepines

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Abstract

Rationale

Benzodiazepines induce electroencephalography (EEG) changes in rodents and humans that are associated with distinct behavioral effects and have been proposed as quantitative biomarkers for GABAA receptor modulation. Specifically, central EEG beta and occipital EEG delta activity have been associated with anxiolysis and sedation, respectively. The extent to which nonhuman primates show the same dose- and topography-dependent effects remained unknown.

Objectives

We aimed at establishing a nonhuman primate model for the evaluation of benzodiazepine EEG pharmacology.

Methods

Four adult male rhesus monkeys were prepared with fully implantable telemetry devices that monitored activity, peripheral body temperature, and contained two EEG (central and occipital), one electromyography (EMG), and one electrooculography channel. We investigated daytime alprazolam-induced changes in EEG spectral power, sleep–wake states, EMG activity, locomotor activity, and body temperature. Alprazolam (0.01–1.8 mg/kg, i.m.) or vehicle was administered acutely, and telemetry recording was conducted for 1 h.

Results

Daytime alprazolam dose-dependently increased central EEG power (including beta activity), increased occipital EEG delta power, and decreased occipital EEG alpha, theta, and sigma power. There was an ~8-fold difference in the potency of alprazolam to increase central EEG beta vs. occipital EEG delta activity (based on relative EEG power). The highest dose, which increased both central EEG beta and occipital EEG delta relative power, induced sedative effects (increased time spent in N1 and N2 sleep stages) and decreased peripheral body temperature and locomotor activity.

Conclusions

Alprazolam induces dose- and topography-dependent EEG changes in rhesus monkeys and provides a valuable model for studying benzodiazepine pharmacology.

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Acknowledgments

The authors thank Megan Fine and Vince Mendenhall for their surgical services and guidance during the animal recovery period. We also thank Troy Velie and Lorie Boyd for assistance with the use of DSI hardware and software. The authors thank Megan Follett and Joseph Talley for technical assistance and Chris Young for assistance with data analysis. Finally, we thank the veterinary staff from the UMMC Center for Comparative Research for their valuable help during the establishment of this model/procedure and for their constant care for our animals.

Funding

This work was supported by the National Institutes of Health (DA011792, DA043204, DA046778, and DA049886).

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Authors and Affiliations

  1. Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, 2500 N State St, Jackson, MS, 39216, USA

    Lais F. Berro, John S. Overton, Jaren A. Reeves-Darby & James K. Rowlett

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  1. Lais F. Berro
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  2. John S. Overton
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  3. Jaren A. Reeves-Darby
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  4. James K. Rowlett
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Contributions

LFB and JKR were responsible for the study concept and design. LFB and JRD contributed to the acquisition of data. LFB, JSO, and JKR assisted with data analysis and interpretation of findings. LFB and JKR drafted the manuscript. All authors read and provided critical revision of the manuscript for important intellectual content and approved the final version for publication.

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Correspondence to Lais F. Berro.

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This article belongs to a Special Issue on Imaging for CNS drug development and biomarkers

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Berro, L.F., Overton, J.S., Reeves-Darby, J.A. et al. Alprazolam-induced EEG spectral power changes in rhesus monkeys: a translational model for the evaluation of the behavioral effects of benzodiazepines. Psychopharmacology 238, 1373–1386 (2021). https://doi.org/10.1007/s00213-021-05793-z

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