Benzodiazepine site agonists differentially alter acetylcholine release in rat amygdala

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

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1293-1300
Number of pages8
JournalAnesthesia and analgesia
Volume118
Issue number6
DOIs
StatePublished - Jan 1 2014

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Amygdala
Benzodiazepines
Acetylcholine
Midazolam
Confidence Intervals
Diazepam
Dialysis
Cholinergic Agonists
Eszopiclone
Isoflurane
Microdialysis
Sleep Initiation and Maintenance Disorders
Synaptic Transmission
Cholinergic Agents
Sprague Dawley Rats
Anxiety
Anesthesia
High Pressure Liquid Chromatography
Acids

All Science Journal Classification (ASJC) codes

  • Anesthesiology and Pain Medicine

Cite this

Benzodiazepine site agonists differentially alter acetylcholine release in rat amygdala. / Hambrecht-Wiedbusch, Viviane S.; Mitchell, Melinda F.; Firn, Kelsie A.; Baghdoyan, Helen; Lydic, Ralph.

In: Anesthesia and analgesia, Vol. 118, No. 6, 01.01.2014, p. 1293-1300.

Research output: Contribution to journalArticle

Hambrecht-Wiedbusch, Viviane S. ; Mitchell, Melinda F. ; Firn, Kelsie A. ; Baghdoyan, Helen ; Lydic, Ralph. / Benzodiazepine site agonists differentially alter acetylcholine release in rat amygdala. In: Anesthesia and analgesia. 2014 ; Vol. 118, No. 6. pp. 1293-1300.
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abstract = "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.",
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AU - Mitchell, Melinda F.

AU - Firn, Kelsie A.

AU - Baghdoyan, Helen

AU - Lydic, Ralph

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N2 - 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.

AB - 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.

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