Benzodiazepine site agonists differentially alter acetylcholine release in rat amygdala.
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.
Viviane S
VS
Hambrecht-Wiedbusch
Melinda F
MF
Mitchell
Kelsie A
KA
Firn
Helen A
HA
Baghdoyan
Ralph
R
Lydic
D000109:Acetylcholine / Q000378:metabolism*; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism*; D000769:Anesthesia, Inhalation; D018685:Anesthetics, Inhalation; D000818:Animals; D053961:Azabicyclo Compounds / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003975:Diazepam / Q000494:pharmacology; D000069582:Eszopiclone; D018755:GABA Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D007275:Injections, Intravenous; D007530:Isoflurane; D008297:Male; D017551:Microdialysis; D008874:Midazolam / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects*; D000077334:Zolpidem
D018685:Anesthetics, Inhalation; D053961:Azabicyclo Compounds; D018755:GABA Agonists; D010879:Piperazines; D011725:Pyridines; D011963:Receptors, GABA-A; D000077334:Zolpidem; D007530:Isoflurane; D000109:Acetylcholine; D003975:Diazepam; D008874:Midazolam; D000069582:Eszopiclone