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Benzodiazepine Site Agonists Differentially Alter Acetylcholine Release in Rat Amygdala

Hambrecht-Wiedbusch, Viviane S. PhD; Mitchell, Melinda F. BBA; Firn, Kelsie A. BS; Baghdoyan, Helen A. PhD; Lydic, Ralph PhD

doi: 10.1213/ANE.0000000000000201
Neuroscience in Anesthesiology and Perioperative Medicine: Research Report

BACKGROUND: Agonist binding at the benzodiazepine site of γ-aminobutric acid type A receptors diminishes anxiety and insomnia by actions in the amygdala. The neurochemical effects of benzodiazepine site agonists remain incompletely understood. Cholinergic neurotransmission modulates amygdala function, and this study tested the hypothesis that benzodiazepine site agonists alter acetylcholine (ACh) release in the amygdala.

METHODS: Microdialysis and high-performance liquid chromatography quantified ACh release in the amygdala of Sprague-Dawley rats (n = 33). ACh was measured before and after IV administration (3 mg/kg) of midazolam or eszopiclone, with and without anesthesia. ACh in isoflurane-anesthetized rats during dialysis with Ringer’s solution (control) was compared with ACh release during dialysis with Ringer’s solution containing (100 μM) midazolam, diazepam, eszopiclone, or zolpidem.

RESULTS: In unanesthetized rats, ACh in the amygdala was decreased by IV midazolam (−51.1%; P = 0.0029; 95% confidence interval [CI], −73.0% to −29.2%) and eszopiclone (−39.6%; P = 0.0222; 95% CI, −69.8% to −9.3%). In anesthetized rats, ACh in the amygdala was decreased by IV administration of midazolam (−46.2%; P = 0.0041; 95% CI, −67.9% to −24.5%) and eszopiclone (−34.0%; P = 0.0009; 95% CI, −44.7% to −23.3%), and increased by amygdala delivery of diazepam (43.2%; P = 0.0434; 95% CI, 2.1% to 84.3%) and eszopiclone (222.2%; P = 0.0159; 95% CI, 68.5% to 375.8%).

CONCLUSIONS: ACh release in the amygdala was decreased by IV delivery of midazolam and eszopiclone. Dialysis delivery directly into the amygdala caused either increased (eszopiclone and diazepam) or likely no significant change (midazolam and zolpidem) in ACh release. These contrasting effects of delivery route on ACh release support the interpretation that systemically administered midazolam and eszopiclone decrease ACh release in the amygdala by acting on neuronal systems outside the amygdala.

From the Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan.

Accepted for publication January 9, 2014.

Melinda F. Mitchell, BBA, is currently affiliated with Wayne State University School of Medicine, Detroit, Michigan.

Kelsie A. Firn, BS, is currently affiliated with Grand Valley State University, Grand Rapids, Michigan.

Funding: Supported by grants HL65272 (RL) and MH45361 (HAB) from the National Institutes of Health, Bethesda, MD, and by the Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Ralph Lydic, PhD, Department of Anesthesiology, University of Michigan, 7433 Medical Science Building I, 1150 West Medical Center Dr., Ann Arbor, MI 48109-5615. Address e-mail to rlydic@umich.edu

© 2014 International Anesthesia Research Society