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A therapeutic dose of zolpidem reduces thalamic GABA in healthy volunteers: a proton MRS study at 4 T

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Abstract

Background

Zolpidem is a nonbenzodiazepine sedative/hypnotic that acts at GABAA receptors to influence inhibitory neurotransmission throughout the central nervous system. A great deal is known about the behavioral effects of this drug in humans and laboratory animals, but little is known about zolpidem’s specific effects on neurochemistry in vivo.

Objectives

We evaluated how acute administration of zolpidem affected levels of GABA, glutamate, glutamine, and other brain metabolites.

Materials and methods

Proton magnetic resonance spectroscopy (1H MRS) at 4 T was employed to measure the effects of zolpidem on brain chemistry in 19 healthy volunteers. Participants underwent scanning following acute oral administration of a therapeutic dose of zolpidem (10 mg) in a within-subject, single-blind, placebo-controlled, single-visit study. In addition to neurochemical measurements from single voxels within the anterior cingulate (ACC) and thalamus, a series of questionnaires were administered periodically throughout the experimental session to assess subjective mood states.

Results

Zolpidem reduced GABA levels in the thalamus, but not the ACC. There were no treatment effects with respect to other metabolite levels. Self-reported ratings of “dizzy,” “nauseous,” “confused,” and “bad effects” were increased relative to placebo, as were ratings on the sedation/intoxication (PCAG) and psychotomimetic/dysphoria (LSD) scales of the Addiction Research Center Inventory. Moreover, there was a significant correlation between the decrease in GABA and “dizzy.”

Conclusions

Zolpidem engendered primarily dysphoric-like effects and the correlation between reduced thalamic GABA and “dizzy” may be a function of zolpidem’s interaction with α1GABAA receptors in the cerebellum, projecting through the vestibular system to the thalamus.

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Acknowledgements

The authors thank R. Ross MacLean for his expert assistance. The authors also thank Dr. George Trksak for the helpful discussion regarding statistical analyses. This study was funded by the National Institutes on Drug Abuse grants K01 DA023659 (Dr. Licata), K05 DA000343 (Dr. Lukas), and K24 DA151116 (Dr. Renshaw). The authors have no financial relationships with the National Institutes on Drug Abuse. The experiments described herein complied with the current laws of the United States of America.

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Authors and Affiliations

  1. Behavioral Psychopharmacology Research Laboratory, McLean Hospital/Harvard Medical School, 115 Mill Street, Belmont, MA, 02478, USA

    Stephanie C. Licata, David M. Penetar & Scott E. Lukas

  2. Brain Imaging Center, McLean Hospital/Harvard Medical School, 115 Mill Street, Belmont, MA, 02478, USA

    J. Eric Jensen, Andrew P. Prescot & Scott E. Lukas

  3. Brain Institute and Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, 84132, USA

    Perry F. Renshaw

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  1. Stephanie C. Licata
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  2. J. Eric Jensen
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Correspondence to Stephanie C. Licata.

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Licata, S.C., Jensen, J.E., Penetar, D.M. et al. A therapeutic dose of zolpidem reduces thalamic GABA in healthy volunteers: a proton MRS study at 4 T. Psychopharmacology 203, 819–829 (2009). https://doi.org/10.1007/s00213-008-1431-1

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