THERE IS A NEED TO CLARIFY NEUROCHEMICAL MECHANISMS UNDERLYING SLEEP APNEA, SUCH AS THE ROLE OF MONOAMINE NEUROTRANSMITTERS, IN the context of pharmacotherapy. Sleep apnea syndrome

THERE IS A NEED TO CLARIFY NEUROCHEMICAL MECHANISMS UNDERLYING SLEEP APNEA, SUCH AS THE ROLE OF MONOAMINE NEUROTRANSMITTERS, IN the context of pharmacotherapy. Sleep apnea syndrome is estimated to affect 4% of men and 2% of women in the middle-aged work force population in the United States.1 It is associated with reduced daytime vigilance and an increased risk of cardiovascular disease. Sleep apneas are classified into 3 types: obstructive, central, and mixed.2 Obstructive sleep apneas are characterized by repetitive obstructions of the upper airway with increased respiratory effort, whereas central sleep apneas occur in the absence of respiratory effort, and mixed apneas begin as central but continue as obstructive. Current mechanical and surgical therapies carry significant morbidity or discomfort. The monoamine serotonin (5-HT) is known to have an important role in the control of ventilation in humans.3,4 One early report suggested that L-tryptophan, a 5-HT precursor, may have a beneficial effect in the treatment of obstructive (but not central) sleep apnea.5 More recently, fluoxetine and paroxetine, 2 selective serotonin reuptake inhibitors (SSRIs), were demonstrated to benefit some patients with obstructive apnea.6 In the same manner, patients with obstructive apnea syndrome showed therapeutic response to mirtazapine, an antidepressant with serotonergic (5-HT1 receptor agonistic but 5-HT2,3 receptor antagonistic) effects. 7 In a study on sudden infant death syndrome (SIDS), it was shown that in regions of the medulla, the number and density of 5-HT neurons were higher and the density of 5-HT1A receptors labeled with [3H]8-OH-DPAT was lower in SIDS victims than in controls.8 In Sprague-Dawley rats, intraperitoneal administration of 5HT, which does not penetrate the blood-brain barrier (BBB), increases apnea index by at least 250% during rapid eye movement sleep (REMS),9 whereas administration of the 5-HT3 receptor antagonist GR38032F reduces apnea expression during slow wave sleep (SWS) and REMS.10 Similarly, mirtazapine reduces central apnea expression during SWS and REMS.11 This supports the clinical relevance of studying central sleep apneas in rodents, notably because most patients with sleep apnea syndrome exhibit a combination of the 3 types of sleep apneas. During SWS and REMS, wild-type (129/Sv) mice show central apneic episodes, typically accompanied by the disappearance of intercostal electromyogram bursts (absence of respiratory efforts). 12 In this mouse, the 5-HT2A receptor inhibitor MDL 100907 decreases the index of central apneas during SWS.13 To further investigate the role of endogenous 5-HT in central sleep apnea, we examined breathing during sleep in transgenic (Tg8) mice that display increased monoamine levels as a result of a genetic lack of monoamine oxidase A (MAOA), an important enzyme in the degradation of monoamines such as 5-HT and norepinephrine (NE). 14-17 At the same time, because 5-HT is involved in sleep state regulation,18 we evaluated the effect of this genetic deficiency on vigilance state distribution. We found that sleep apnea indices were significantly higher in Tg8 mice than in their wild-type controls. We also studied sleep and breathing after acute administration of the MAOA inhibitor clorgyline. Finally, we assessed the role of 5-HT in sleep apnea genesis, by lowering 5-HT synthesis with p-chlorophenylalanine, without changing whole-brain NE concentration, in both mutant and wild-type mice. Our results suggest that excess endogenous 5-HT facilitates sleep apnea. Sleep Apneas are Increased in Mice Lacking Monoamine Oxidase A Caroline Real1; Daniela Popa, PhD2,3; Isabelle Seif, PhD1; Jacques Callebert, PharmD, PhD4; Jean-Marie Launay, PharmD, PhD4 ; Joëlle Adrien, PhD2,3; Pierre Escourrou, MD, PhD1