GABA(A) receptors in the pontine reticular formation of C57BL/6J mouse modulate neurochemical, electrographic, and behavioral phenotypes of wakefulness.
Drugs that potentiate transmission at GABA(A) receptors are widely used to enhance sleep and to cause general anesthesia. The mechanisms underlying these effects are unknown. This study tested the hypothesis that GABA(A) receptors in the pontine reticular nucleus, oral part (PnO) of mouse modulate five phenotypes of arousal: sleep and wakefulness, cortical electroencephalogram (EEG) activity, acetylcholine (ACh) release in the PnO, breathing, and recovery time from general anesthesia. Microinjections into the PnO of saline (vehicle control), the GABA(A) receptor agonist muscimol, muscimol with the GABA(A) receptor antagonist bicuculline, and bicuculline alone were performed in male C57BL/6J mice (n = 33) implanted with EEG recording electrodes. Muscimol caused a significant increase in wakefulness and decrease in rapid eye movement (REM) and non-REM (NREM) sleep. These effects were reversed by coadministration of bicuculline. Bicuculline administered alone caused a significant decrease in wakefulness and increase in NREM sleep and REM sleep. Muscimol significantly increased EEG power in the delta range (0.5-4 Hz) during wakefulness and in the theta range (4-9 Hz) during REM sleep. Dialysis delivery of bicuculline to the PnO of male mice (n = 18) anesthetized with isoflurane significantly increased ACh release in the PnO, decreased breathing rate, and increased anesthesia recovery time. All drug effects were concentration dependent. The effects on phenotypes of arousal support the conclusion that GABA(A) receptors in the PnO promote wakefulness and suggest that increasing GABAergic transmission in the PnO may be one mechanism underlying the phenomenon of paradoxical behavioral activation by some benzodiazepines.
Flint
RaShonda R
RR
Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Chang
Theresa
T
Lydic
Ralph
R
Baghdoyan
Helen A
HA
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001640:Bicuculline / Q000008:administration & dosage; D004569:Electroencephalography / Q000187:drug effects; D058785:GABA-A Receptor Agonists; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017551:Microdialysis; D008845:Microinjections; D009118:Muscimol / Q000008:administration & dosage; D010641:Phenotype; D011149:Pons / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D011963:Receptors, GABA-A / Q000235:genetics / Q000502:physiology*; D012154:Reticular Formation / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014851:Wakefulness / Q000235:genetics / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D058785:GABA-A Receptor Agonists; D011963:Receptors, GABA-A; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; D001640:Bicuculline