Benzodiazepine receptor agonists cause drug-specific and state-specific alterations in EEG power and acetylcholine release in rat pontine reticular formation.
OBJECTIVE
Benzodiazepine (BDZ) and non-benzodiazepine (NBDZ) hypnotics enhance GABAergic transmission and are widely used for the treatment of insomnia. In the pontine reticular formation (PRF), GABA inhibits rapid eye movement (REM) sleep and acetylcholine (ACh) release. No previous studies have characterized the effects of BDZ and NBDZ hypnotics on ACh release in the PRF. This study tested 2 hypotheses: (1) that microdialysis delivery of zolpidem, eszopiclone, and diazepam to rat PRF alters ACh release in PRF and electroencephalographic (EEG) delta power and (2) that intravenous (i.v.) administration of eszopiclone to non-anesthetized rat alters ACh release in the PRF, sleep, and EEG delta power.


METHODS
A within- and between-groups experimental design.


METHODS
University of Michigan.


METHODS
Adult male Crl:CD*(SD) (Sprague-Dawley) rats (n = 57).


METHODS
In vivo microdialysis of the PRF in rats anesthetized with isoflurane was used to derive the concentration-response effects of zolpidem, eszopiclone, and diazepam on ACh release. Chronically instrumented rats were used to quantify the effects of eszopiclone (3 mg/kg, i.v.) on ACh release in the PRF, sleep-wake states, and cortical EEG power.


RESULTS
ACh release was significantly increased by microdialysis delivery to the PRF of zolpidem and eszopiclone but not diazepam. EEG delta power was increased by zolpidem and diazepam but not by eszopiclone administered to the PRF. Eszopiclone (i.v.) decreased ACh release in the PRF of both anesthetized and non-anesthetized rats. Eszopiclone (i.v.) prevented REM sleep and increased EEG delta power.


CONCLUSIONS
The concentration-response data provide the first functional evidence that multiple GABA(A) receptor subtypes are present in rat PRF. Intravenously administered eszopiclone prevented REM sleep, decreased ACh release in the PRF, and increased EEG delta power. The effects of eszopiclone are consistent with evidence that ACh release in the PRF is lower during NREM sleep than during REM sleep, and with data showing that cholinergic stimulation of the PRF activates the cortical EEG.
Hambrecht-Wiedbusch
Viviane S
VS
Department of Anesthesiology, University of Michigan, 7433 Medical Science Building 1, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5615, USA.
Gauthier
Elizabeth A
EA
Baghdoyan
Helen A
HA
Lydic
Ralph
R
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D053961:Azabicyclo Compounds / Q000494:pharmacology; D001921:Brain / Q000187:drug effects*; D003975:Diazepam / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects*; D000069582:Eszopiclone; D018755:GABA Agonists / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D010879:Piperazines / Q000494:pharmacology; D011149:Pons / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects*; D012154:Reticular Formation / Q000187:drug effects; D012894:Sleep Stages / Q000187:drug effects; D000077334:Zolpidem
D053961:Azabicyclo Compounds; D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; D006993:Hypnotics and Sedatives; D010879:Piperazines; D011725:Pyridines; D011963:Receptors, GABA-A; D000077334:Zolpidem; D000109:Acetylcholine; D003975:Diazepam; D000069582:Eszopiclone