Acute administration of the novel serotonin and noradrenaline reuptake inhibitor, S33005, markedly modifies sleep-wake cycle architecture in the rat.
BACKGROUND
The interrelationship between depressive states and sleep-wake cycle architecture is characterised by a decreased latency to the first paradoxical sleep (PS) episode, together with an enhancement of PS during the first part of the night. Conversely, slow-wave sleep (SWS) is decreased and intermittent awakenings increased. Notably, antidepressant treatment is generally associated with a diminution of PS.


OBJECTIVE
In light of these observations, we examined the influence of acute administration of the novel mixed serotonin-noradrenaline reuptake blocker, (-)1-(1-dimethylaminomethyl 5-methoxybenzocyclobutan-1-yl)-cyclohexanol HCl (S33005), upon sleep-wake architecture in rats.


METHODS
Animals were injected with vehicle or incremental doses of S33005 at the onset of either the dark or light periods. Digitised polygraphic recordings were performed, and changes evoked by S33005 were determined over 24-h recording periods, i.e., number and duration of sleep-wake episodes, latencies to PS and SWS, power band spectra of the electroencephalogram (EEG) and circadian changes.


RESULTS
At 0.04 mg/kg, S33005 was inactive, whereas at 0.63 mg/kg, it modestly increased PS latencies and diminished PS duration during the light period. At 10 mg/kg, S33005 reduced markedly PS duration for about 4-h when injected prior to both light and dark periods. Latency to PS was prolonged, and the circadian acrophase was delayed. These effects are in keeping with previous studies of monoamine reuptake inhibitors, but, notably, SWS duration was increased when S33005 was injected at the onset of the light phase (+4%). These changes occurred without marked modifications in circadian rhythmicity or EEG spectral band power. Finally, even at the highest dose of S33005, only a limited rebound of SWS (+5%) and PS (+10%) was apparent. Amongst antidepressant to date examined, this is an original profile of influence upon sleep patterns.


CONCLUSIONS
These results demonstrate a pattern of influence of S33005 upon sleep-wake architecture in rats which is globally consistent with antidepressant properties, but with a distinctive enhancement of restorative slow-wave sleep.
EA 3734 & IFR19, C. Bernard Univ., 8 av. Rockefeller, 69373, Lyon Cedex 08, France. cespuglio@univ-lyon1.fr
Raymond
R
Cespuglio
Colette
C
Rousset
Gabriel
G
Debilly
Catherine
C
Rochat
Mark J
MJ
Millan
D000322:Adrenergic Agonists / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects; D002940:Circadian Rhythm / Q000187:drug effects; D003511:Cyclohexanols / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D005583:Fourier Analysis; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D012815:Signal Processing, Computer-Assisted; D012890:Sleep / Q000187:drug effects*; D012894:Sleep Stages / Q000187:drug effects; D014851:Wakefulness / Q000187:drug effects*
D000322:Adrenergic Agonists; D000928:Antidepressive Agents; D003511:Cyclohexanols; D009638:Norepinephrine; D017367:Selective Serotonin Reuptake Inhibitors; C432168:1-(1-dimethylaminomethyl-5-methoxybenzocyclobutan-1-yl)cyclohexanol