Pontine reticular formation (PnO) administration of hypocretin-1 increases PnO GABA levels and wakefulness.
OBJECTIVE
GABAergic transmission in the oral part of the pontine reticular formation (PnO) increases wakefulness. The hypothalamic peptide hypocretin-1 (orexin A) promotes wakefulness, and the PnO receives hypocretinergic input. The present study tested the hypothesis that PnO administration of hypocretin-1 increases PnO GABA levels and increases wakefulness. This study also tested the hypothesis that wakefulness is either increased or decreased, respectively, by PnO administration of drugs known to selectively increase or decrease GABA levels.


METHODS
Awithin-subjects design was used for microdialysis and microinjection experiments.


METHODS
University of Michigan.


METHODS
Experiments were performed using adult male Crl:CD (SD)IGS BR (Sprague-Dawley) rats (n=46).


METHODS
PnO administration of hypocretin-1, nipecotic acid (a GABA uptake inhibitor that increases extracellular GABA levels), 3-mercaptopropionic acid (a GABA synthesis inhibitor that decreases extracellular GABA levels; 3-MPA), and Ringer solution (vehicle control).


RESULTS
Dialysis administration of hypocretin-1 to the PnO caused a statistically significant, concentration-dependent increase in PnO GABA levels. PnO microinjection of hypocretin-1 or nipecotic acid caused a significant increase in wakefulness and a significant decrease in non-rapid eye movement (NREM) sleep and REM sleep. Microinjecting 3-MPA into the PnO caused a significant increase in NREM sleep and REM sleep and a significant decrease in wakefulness.


CONCLUSIONS
An increase or a decrease in PnO GABA levels causes an increase or decrease, respectively, in wakefulness. Hypocretin-1 may promote wakefulness, at least in part, by increasing GABAergic transmission in the PnO.
Watson
Christopher J
CJ
Department ofAnesthesiology, University ofMichigan, Ann Arbor, MI 48109-5615, USA.
Soto-Calderon
Haideliza
H
Lydic
Ralph
R
Baghdoyan
Helen A
HA
D000818:Animals; D001143:Arousal / Q000502:physiology; D001831:Body Temperature; D007267:Injections; D047908:Intracellular Signaling Peptides and Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D009479:Neuropeptides / Q000008:administration & dosage / Q000494:pharmacology*; D000068797:Orexins; D011149:Pons / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012154:Reticular Formation / Q000187:drug effects* / Q000378:metabolism*; D007319:Sleep Initiation and Maintenance Disorders / Q000139:chemically induced; D012895:Sleep, REM / Q000187:drug effects; D014851:Wakefulness / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000187:drug effects* / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D005680:gamma-Aminobutyric Acid