NEUROCHEMISTRY OF SLEEP Early experimental studies that focused on the Ralph nuclei of the brainstem appeared to implicate serotonin

as the primary sleep promoting neurotransmitter, while catecholamines were considered to be responsible for wakefulness.simple neurochemical models have given way to more complex formulations involving multiple parallel waking systems. Pharmacologic studies suggests that histamine,acetylcholine, dopamine , serotonine and noradrenaline are all involved in wake promotion. In addition pontine cholinergic neurotransmission is known to play a role in REM sleep generation. The alerting influence of caffeine implicates adenosine, where as the hypnotic effects of benzodiazepines and barbiturates suggests a role for endogenous ligands of the GABAA receptor complex. A newly characterized neuropeptide , hypocretin(orexin) has recently been implicated in the pathophysiology of narcolepsy but its role in normal sleep regulation remains to be defiened. A variety of sleep promoting substances have been identified, although it is not known whether they are involved in the endogenous sleep-wake regulatory process. These include prostaglandin D2, delta sleep inducing peptide,muramyl dipeptide , interleukin 1, fatty acid primary amides, and melatonin. The hypnotic effect of these substances is commonly limited to NREM or slow-wave sleep, although peptides that increase REM sleep have also been reported. Many putative sleep factors including interleukin 1 and prostaglandin D2 are immunologically active as well, suggesting a link between immune function and sleep-wake states. BEHAVIOURAL CORELATES OF SLEEP STATES AND STAGES Polysomnographic staging of sleep correlates with behavioural changes during specific states and stages. During the transitional stage between wakefulness and sleep (stage 1) subjects may respond to

faint auditory or visual signals without awakening. Memory incorporation is inhibited at the onset of NREM stage 1 sleep, which may explain why individuals aroused from that transitional sleep stage frequently deny having been asleep. Such transitions may intrude upon behavioural wakefulness after sleep deprivation, not withstanding attempts to remain continuously awake. Awakenings from REM sleep are associated with recall of vivid dream imagery > 80% of time. Imagery may also be reported after NREM sleep interruptions but with less details and vividness. The incidence of NREM sleep recall can be increased by selective REM sleep deprivation suggesting that REM sleep and dreaming per se are not inexorably linked. PHYSIOLOGIC CORRELATES OF SLEEP STATES AND STAGES All majr physiologic systems are influenced by sleep. Changes in cardiovascular function includes a decrease in blood pressure and heart rate during NREM and particularly during slow-wave sleep. These changes are mediated principally by the vagus. Respiratory rate becomes more regular during NREM sleep and tonic REM sleep and becomes very irregular during phasic REM sleep. Minute ventilation decreases in NREM sleep out of proportion to the decrease in metabolic rate at sleep onset, resulting in a higher pco2. Endocrine function also varies with sleep. Slow wave sleep is associated with secretion of growth hormone while sleep in general is associated with augmented secretion of prolactin. During puberty sleep is associated with increased secretion of LH whereas sleep in the postpubertal females inhibits LH secretion in the early follicular phase of the menstrual cycle. Sleep onset is associated with inhibition of thyroid stimulating hormone and of the adrenocorticorticotropic hormone-cortisol axis, an effect that is superimposed on the prominent circadianrhythms in the two systems.

Sleep is also accompanied by alterations of thermoregulatory function. NREM sleep is associated with an attenuation of thermoregulatory function. NREM sleep is associated with an attenuation of thermoregulatory responses to either heat or cold stress. REM sleepis associated with complete absence of thermoregulatory responsiveness, effectively resulting in functional poikilothermy. However the potential adverse impact of this failure of thermoregulation is blunted by inhibition of REM sleep by extreme ambient temperatures.