Serotonin and sleep

TY - CHAP

T1 - Serotonin and sleep

AU - Tricklebank, Mark D.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - The modulation of sleep states has long been associated with serotonergic activity since it was noted that arousal closely correlates with the firing rate of dorsal raphe neurons. The pharmacological tools for investigating serotonin metabolism became more selective with respect to affinity for the many subtypes of serotonin receptor. The most commonly used serotoninergic drugs, the SSRIs, have been found to strongly suppress rapid eye movement (REM) sleep. The injection of serotonin into the cat lateral ventricle elicited first arousal followed by prolonged synchronous discharges characteristic of slow-wave sleep. Injecting serotonin toxins showed a reduction in sleep in parallel with the reduction in serotonin content. The depletion of serotonin using para chlorophenyl alanine also markedly reduced sleep, which is readily reversed by administration of 5-hydroxytryptophan. In contrast the indoleamine melatonin can ameliorate sleep disturbance. Compounds with high affinity for the 5-HT2A receptor increase slow-wave sleep in both man and animals. The supracuprachiasmatic nucleus in the hypothalamus functions as a master circadian pacemaker. Mutant fruit files have demonstrated that circadian rhythms are heritable, some strains being arrhythmic, while others showing periodicity in excess of 24 hours. These observations gave rise to the concept of the existence of clock genes with the hypothetical master gene termed Period. An antibody to period has been obtained, which showed that there was a 24 hours cycling in the amount of period protein expressed. Period is a nuclear protein which shuttles between the cell nucleus and cytoplasm in a temporally regulated manner which is abolished in the timeless mutant. It has been suggested that melatonin secreted from the pineal gland serves as a temporal feedback on the oscillator since the suprachiasmatic nucleus regulating circadian phase and maintaining rhythm stability. Compounds with affinity and selectivity for 5-HT6 and 5-HT7 receptors are prime candidates for influencing sleep. 5-HT7 is strongly expressed in the suprachiasmatic nucleus and an agonist action at the receptor increases wakefulness and reduces REM sleep. The selective 5-HT6 receptor antagonist Ro4368554 reduces sleep latency and wakefulness. It is surely significant that there is a very strong relationship between sleep disturbance and depression with 50%-60% of young adults with depression having sleep disturbance perhaps linking serotonin to the underlying the antidepressant effects of sleep deprivation. Sleep electrosomnography is a key tool in the clinical profiling of any new serotonergic compound.

AB - The modulation of sleep states has long been associated with serotonergic activity since it was noted that arousal closely correlates with the firing rate of dorsal raphe neurons. The pharmacological tools for investigating serotonin metabolism became more selective with respect to affinity for the many subtypes of serotonin receptor. The most commonly used serotoninergic drugs, the SSRIs, have been found to strongly suppress rapid eye movement (REM) sleep. The injection of serotonin into the cat lateral ventricle elicited first arousal followed by prolonged synchronous discharges characteristic of slow-wave sleep. Injecting serotonin toxins showed a reduction in sleep in parallel with the reduction in serotonin content. The depletion of serotonin using para chlorophenyl alanine also markedly reduced sleep, which is readily reversed by administration of 5-hydroxytryptophan. In contrast the indoleamine melatonin can ameliorate sleep disturbance. Compounds with high affinity for the 5-HT2A receptor increase slow-wave sleep in both man and animals. The supracuprachiasmatic nucleus in the hypothalamus functions as a master circadian pacemaker. Mutant fruit files have demonstrated that circadian rhythms are heritable, some strains being arrhythmic, while others showing periodicity in excess of 24 hours. These observations gave rise to the concept of the existence of clock genes with the hypothetical master gene termed Period. An antibody to period has been obtained, which showed that there was a 24 hours cycling in the amount of period protein expressed. Period is a nuclear protein which shuttles between the cell nucleus and cytoplasm in a temporally regulated manner which is abolished in the timeless mutant. It has been suggested that melatonin secreted from the pineal gland serves as a temporal feedback on the oscillator since the suprachiasmatic nucleus regulating circadian phase and maintaining rhythm stability. Compounds with affinity and selectivity for 5-HT6 and 5-HT7 receptors are prime candidates for influencing sleep. 5-HT7 is strongly expressed in the suprachiasmatic nucleus and an agonist action at the receptor increases wakefulness and reduces REM sleep. The selective 5-HT6 receptor antagonist Ro4368554 reduces sleep latency and wakefulness. It is surely significant that there is a very strong relationship between sleep disturbance and depression with 50%-60% of young adults with depression having sleep disturbance perhaps linking serotonin to the underlying the antidepressant effects of sleep deprivation. Sleep electrosomnography is a key tool in the clinical profiling of any new serotonergic compound.

KW - Sleep electrosomnography arousal REM sleep

KW - Slow wave sleep orexin

UR - http://www.scopus.com/inward/record.url?scp=85081914581&partnerID=8YFLogxK

U2 - 10.1016/B978-0-12-813323-1.00010-4

DO - 10.1016/B978-0-12-813323-1.00010-4

M3 - Chapter

SN - 9780128133248

SP - 181

EP - 192

BT - The Serotonin System

PB - Elsevier

ER -