To facilitate the genetic study of sleep, we documented that rest behavior in Drosophila melanogaster is a sleep-like state. The animals choose a preferred location, become immobile for periods of up to 157 min at a particular time in the circadian day, and are relatively unresponsive to sensory stimuli. Rest is affected by both homeostatic and circadian influences: when rest is prevented, the flies increasingly tend to rest despite stimulation and then exhibit a rest rebound. Drugs acting on a mammalian adenosine receptor alter rest as they do sleep, suggesting conserved neural mechanisms. Finally, normal homeostatic regulation depends on the timeless but not the period central clock gene. Understanding the molecular features of Drosophila rest should shed new light on the mechanisms and function of sleep.

In the fruit fly, Drosophila melanogaster, rest shares features with mammalian sleep, including prolonged immobility, decreased sensory responsiveness and a homeostatic rebound after deprivation. To understand the molecular regulation of sleep-like rest, we investigated the involvement of a candidate gene, cAMP response-element binding protein (CREB). The duration of rest was inversely related to cAMP signaling and CREB activity. Acutely blocking CREB activity in transgenic flies did not affect the clock, but increased rest rebound. CREB mutants also had a prolonged and increased homeostatic rebound. In wild types, in vivo CREB activity increased after rest deprivation and remained elevated for a 72-hour recovery period. These data indicate that cAMP signaling has a non-circadian role in waking and rest homeostasis in Drosophila.

Recent studies have shown excitatory effects of serotonin on upper airway motoneurons. This excitatory effect is normally present and arises from cells in the caudal raphe nuclei. The firing of these serotonergic neurons is reduced during sleep. To determine the importance of serotonin in the maintenance of patient airways and normal respiration in waking in obstructive sleep apnea, we studied the effects of two serotonin antagonists on upper airway dilator muscle activity, diaphragm activity, Sao2, and upper airway cross-sectional area in an animal model of sleep-disordered breathing, the English bulldog. Systemic administration of both antagonists resulted in significant reductions in the peak amplitudes of upper airway muscle respiratory bursts (range, 39 to 62% suppression; p < 0.05). Lesser reductions in diaphragm activity were noted (range, 10 to 33% suppression; p < 0.05). Oxyhemoglobin saturations also fell (p < 0.05), coinciding with suppressions in upper airway muscle activity. With reductions in dilator muscle activity, upper airway cross-sectional areas, as measured with cine CT, showed significant inspiratory collapse. These results support the hypothesis that serotonin is important in the maintenance of patent upper airways in obstructive sleep apnea.

Quantitative measurement of cerebral ventricle volume of eight English bulldogs was performed using magnetic resonance (MR) imaging. The mean ventricular volume was 14.8 ml. with a range of 8.6 ml.-38.1 ml. The mean ventricular volume of two beagles was 2.2 ml with a range of 0.7 ml.-3.7 ml. The percent of intracranial volume occupied by ventricle was found to be significantly larger in bulldogs (14.0%; S.D. = 7.9%) than in beagles (Range = 1.0-4.8%). The relationship between the percent of intracranial volume occupied by ventricle and measurements of body weight, age, sex, and various measures of skull anatomy of the bulldog was also determined. The relationship between ventricular volume and neurologic dysfunction was examined. There was a possible trend between high percent of intracranial volume occupied by ventricle and low body weight. This study will serve as a pilot study for examining the relationship between ventricular volume and neurologic disease in bulldogs.

Obstructive sleep apnea hypopnea syndrome (OSAHS) is a prevalent disorder, for which there are no universally effective pharmacotherapeutics. We hypothesized that in OSAHS, excitatory serotoninergic influences are important for maintaining patency of the upper airway in waking, and that in sleep, reduced serotoninergic drive plays a significant role in upper airway collapse and OSAHS. The previously reported small responses in humans with OSAHS to serotoninergics may relate, in part, to study design and the drugs/doses selected. We therefore performed multitrials/dose, multidose, randomized sleep studies testing the effectiveness of a combination of serotoninergics, trazodone, and L-tryptophan, in our animal model of OSAHS, the English bulldog. Trazodone/L-tryptophan caused dose-dependent reductions in respiratory events in non-rapid-eye-movement sleep (NREMS) and rapid-eye-movement sleep (REMS). During NREMS, the respiratory disturbance index (RDI) +/- standard error was 6.3 +/- 1.4 events/h (placebo) and 0.9 +/- 0.3 (highest dose), p < 0.01. During REMS, the RDI was 31.4 +/- 6.1 events/h (placebo) and 11.5 +/- 4.3 (highest dose), p = 0.002. Trazodone/ L-tryptophan dose-dependently reduced sleep fragmentation, p = 0.03, increased sleep efficiency, p = 0.005, enhanced slow-wave sleep, p = 0.0004, and minimized sleep-related suppression of upper airway dilator activity, p < 0.02. Trazodone with L-tryptophan can treat sleep-disordered breathing (SDB) in an animal model of OSAHS; the effectiveness of this therapy may be related to increased upper airway dilator activity in sleep and/or enhanced slow-wave sleep.