Abstract
An endogenous neuroactive steroid, pregnanolone, and an orally available synthetic analog, CCD-3693, were administered to rats at the middle of their circadian activity phase (6 hr after lights off). Electroencephalogram-defined sleep-wake states, locomotor activity and body temperature were concurrently measured 30 hr before and after treatment. Identical procedures were used to test triazolam and zolpidem. Triazolam (0.1–1.6 mg/kg), zolpidem (2.5–10 mg/kg) and the neuroactive steroids (10–30 mg/kg) produced dose-dependent increases in non-rapid eye movement (NREM) sleep. At this dose and time of day (in which the rats were predominantly awake during the 6 hr before treatment) the neuroactive steroids appeared more intrinsically efficacious in promoting NREM sleep than the benzodiazepine ligands. The neurosteroids did not, however, significantly interfere with rapid eye movement sleep and were more selective in reducing (EEG) wakefulness, with relatively less locomotor activity impairment during waking than triazolam and zolpidem. In addition, the benzodiazepine receptor ligands showed distinct “rebound” wakefulness after the NREM sleep-promoting effect subsided, although the neuroactive steroids did not. In addition, in vitro binding studies and in vivo pharmacological data confirmed that CCD-3693 was orally active in standard tests of anxiety, anticonvulsant, loss-of-righting and passive avoidance.
Footnotes
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Send reprint requests to: Dr. Dale M. Edgar, Sleep Disorders Research Center, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 701 Welch Rd. Suite 327, Palo Alto, CA 94304.
- Abbreviations:
- ANOVA
- analysis of variance
- CT
- circadian time
- CNS
- central nervous system
- EEG
- electroencephalogram
- EMG
- electromyogram
- GABA
- γ-aminobutyric acid
- GC-MS
- gas chromatography-mass spectometry
- GRC
- GABAA receptor complex
- HPβCD
- 2-hydroxypropyl-β-cyclodextrin
- LMA
- locomotor activity
- LRR
- loss-of-righting reflex
- ML
- medial-lateral
- NREM
- non-rapid eye movement sleep
- PTZ
- pentyleneteterazol
- REM
- rapid eye movement sleep (paradoxical sleep)
- Tb
- body temperature
- TBPS
- t-butylbicyclophosphorothionate
- pregnanolone
- 3α-hydroxy-5β-pregnan-20-one
- CCD-3693
- 19-nor-3β-trifluromethyl-3α-hydroxy-5β-pregnan-20-one
- Received August 20, 1996.
- Accepted March 5, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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