Noradrenaline sleep

Antidepressants Noradrenaline/5-HT transporters Na+, K+ channels l Noradrenaline/ 5-HT reuptake l Na+ currents t K+ currents l Excitability of peripheral and central neurons Cardiac arrhythmia, myocardial infarction, sedation, nausea, dry mouth, constipation, dizziness, sleep disturbance, blurred vision... 

It is important to emphasise that a lesion of the reticular system disrupts a number of afferent inputs to the cortex. Particularly important in this respect are the mono-aminergic (especially noradrenaline, 5-HT and histamine) and cholinergic pathways. When the ascending inputs from these neurons are destroyed, sleep is passive and not at all like natural sleep which, as detailed above, has distinct phases and depends on brainstem influences on cortical function. How these different neurotransmitters might influence sleep and arousal will be considered next. 

Cape EG and Jones, BE (1998) Differential modulation of high-frequency gamma-electroencephalogram activity and sleep-wake state by noradrenaline and serotonin microinjections into the region of cholinergic basalis neurons. J. Neurosci. 18 2653-2666. 

Some arousal-related neurotransmitters, including noradrenaline, serotonin, and acetylcholine, feed back to inhibit POA sleep-active neurons. This aspect of the system has been reviewed previously (McGinty Szymusiak, 2000 Saper et al., 2001). Therefore, once sleep-active neurons are activated, arousal-related neurons are inhibited, and inhibitory control of sleep-active neurons by arousal systems is reduced. In this way, sleep onset is facilitated. That is, the mutually inhibitory systems can switch more quickly from wake to sleep, and back. These mutually inhibitory interactions also promote stability of both waking and sleep. 

Figure 2.4 Flip-flop switch model of wake and slow wave sleep active systems. Mutually inhibitory connections exist between GABAergic/Galaninergic slow wave sleep active neurons in the ventrolateral preoptic area (VLPO) of the anterior hypothalamus and aminergic neurons in the hypothalamus (histamine (HA) neurons in the tuberomammillary nucleus (TMN)) and brainstem (serotonin (5-HT) neurons in the dorsal raphe (DR) and noradrenaline (NA) neurons in the locus coeruleus (LC)). Orexinergic neurons in the perifornical hypothalamus (PFH) stabilize the waking state via excitation of the waking side of the flip-flop switch (aminergic neurons).

Lena, I., Parrot, S., Deschaux, O. et al. (2005). Variations in extracellular levels of dopamine, noradrenaline, glutamate, and aspartate across the sleep - wake cycle in the medial prefrontal cortex and nucleus accumbens of freely moving rats. J. Neurosci. Res. 81, 891-9. 

Figure 4.2 Model of the network responsible for paradoxical sleep onset and maintenance Abbreviations DRN, dorsal raphe nucleus 5-HT, serotonin LC, locus coeruleus NA, noradrenaline LDT, laterodorsal tegmental nucleus Ach, acetylcholine Me, magnocellular reticular nucleus Gly glycine DPMe, deep mesencephalic reticular nucleus PAG, periaqueductal gray DPGi, dorsal paragigantocellular reticular nucleus PPT, pedunculopontine nucleus PRN, pontine reticular nucleus SLD, sublaterodorsal nucleus Glu, glutamate Pef/HLA perifornical/lateral hypothalamic area Hcrt, hypocretin (i.e. orexin).

Some less obvious phenomena of catecholamine transport and biosynthesis further illustrate the complexities of deciphering how efferents from midbrain dopamine neurons contribute to sleep-wake regulation. The plasma membrane norepinephrine transporter (NET), which is responsible for the uptake of extracellular noradrenaline, can also readily transport dopamine, and does so in vivo. This... 

Grivel, J., Cvetkovic, V., Bayer, L. el al. (2005). The wake-promoting hypocretin/orexin neurons change their response to noradrenaline after sleep deprivation. J. Neurosci 25, 4127-30. 

The most commonly used therapies for anxiety and depression are selective serotonin reuptake inhibitors (SSRIs) and the more recently developed serotonin noradrenaline reuptake inhibitors (SNRIs). SSRIs, which constitute 60% of the worldwide antidepressant and antianxiety market, are frequently associated with sexual dysfunction, appetite disturbances and sleep disorders. Because SSRIs and SNRIs increase 5-HT levels in the brain, they can indirectly stimulate all 14 serotonergic receptor subtypes [2,3], some of which are believed to lead to adverse side effects associated with these drugs. Common drugs for short-term relief of GAD are benzodiazepines. These sedating agents are controlled substances with addictive properties and can be lethal when used in combination with alcohol. The use of benzodiazepines is associated with addiction, dependency and cognitive impairment. 

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