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Effects of Triazolam Microinjections into the Peri-fornicular Region on Sleep in Rats
Wallace B Mendelson Ph.D, Aaron D. Laposky Ph.D
The hypocretin/orexin (Hcrt/OX) receptor-ligand system is involved in the
pathophysiology of narcolepsy/cataplexy and may play a role in the physiologic
regulation of sleep and waking. Most Hcrt/OX neurons are located in the perifornicular
region (PeF) of the posterior hypothalamus. In this study, we explored the
possibility that some pharmacological effects on sleep may also be mediated by this
system, by microinjecting the clinically used benzodiazepine hypnotic triazolam (TR)
into the PeF of rats. Fourteen rats received bilateral microinjections of vehicle and TR
(0.25ug and 0.50 ug) into the PeF, in randomized order, followed by 4 hours of
sleep/wake recordings. Data were analyzed by repeated measures analysis of variance
for dose (vehicle, TR 0.25ug and 0.50ug) and time (hours 1-4) factors. In five additional
rats, TR (0.50 ug) was administered in combination with the Type A .-aminobutyric
acid-benzodiazepine receptor (GABAA-BZD) antagonist, flumazenil (0.95 ug). TR (0.25
and 0.50ug) significantly decreased wake and intermittent wake time and increased
non-rapid eye movement (NREM) and total sleep times in the two hours following
injections. TR (0.25 and 0.50ug) decreased NREM sleep latency and TR (0.25ug)
decreased rapid-eye movement latency. The effects of TR (0.50 ug) were blocked by
flumazenil (0.95 ug). TR significantly enhanced sleep when microinjected into the PeF
region. These data provide a basis for the hypothesis that the function of the Hcrt/OX
system may be altered by exogenously administered benzodiazepines, and potentially
by endogenous ligands of the GABAA-BZD receptor. (Sleep and Hypnosis
2003;5(3):154-162)
Key words: triazolam, flumazenil, peri-fornicular area, sleep, hypothalamus
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