Sub-chronic administration of zolpidem affects modifications to rat sleep architecture.
Gamma-aminobutyric acidA receptor (GABAAR) modulators constitute the majority of clinically relevant sedative-hypnotics. Animal studies have clearly demonstrated sedative efficacy for these compounds in acute studies. However, relatively less is known regarding their efficacy under brief periods of repeat administration or following intermittent dosing. Therefore zolpidem, a short-acting GABAAR modulator with selectivity for the type-I (omega1) benzodiazepine receptor, was studied for efficacy in altering rat sleep architecture as determined by electrocorticogram (ECoG) and electromyogram (EMG) activity over a 7-day sub-chronic administration period. Zolpidem caused significant reductions in wakefulness entries and rapid eye movement (REM) sleep entries and duration, with increases in Delta sleep duration throughout the administration period. Examination of sleep architecture 24 h after cessation of sub-chronic zolpidem administration revealed a decrease in Delta sleep, suggesting that repeated zolpidem administration might elicit enduring modifications to sleep organization. This was not seen following similar dosing of diazepam. The efficacy of sub-chronic administration of zolpidem to alter sleep architecture was enhanced when the administration regimen was repeated following a 7-day hiatus. Significant increases in Delta sleep duration, with significant decreases in light sleep and wakefulness were observed during the repeated exposure to zolpidem. Therefore, sub-chronic administration of zolpidem affected lasting modifications in sleep organization that appeared both 1 day following administration and during reiterated administration without eliciting tolerance.
Renger
John J
JJ
Department of Molecular Neurology, Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486, USA. john_renger@merck.com
Dunn
Susan L
SL
Motzel
Sherri L
SL
Johnson
Colena
C
Koblan
Kenneth S
KS
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D003975:Diazepam / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004334:Drug Administration Schedule; D004569:Electroencephalography / Q000187:drug effects; D004576:Electromyography; D018755:GABA Agonists / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D008297:Male; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D011963:Receptors, GABA-A / Q000378:metabolism; D012890:Sleep / Q000187:drug effects* / Q000502:physiology; D012895:Sleep, REM / Q000187:drug effects / Q000502:physiology; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology; D000077334:Zolpidem; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; D011725:Pyridines; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D000077334:Zolpidem; D003975:Diazepam