Neurochemical regulation of sleep

Depression as a spreading adjustment disorder of monoaminergic neurons: a case for primary implication of the locus coeruleus.

Selective serotonin reuptake inhibitors, such as fluoxetine (FLX), are the most commonly used drugs in the treatment of major depression. However, there is a limited understanding of their molecular mechanism of action. Although the acute effect of selective serotonin reuptake inhibitors in elevating synaptic serotonin concentrations is well known, the clinical amelioration of depressive symptoms requires 14-21 days of treatment, suggesting that numerous other rearrangements of function in the CNS must take place. In the present study, we demonstrated that 14 days of FLX treatment up-regulated galanin mRNA levels by 100% and GalR2-binding sites by 50%, in the rat dorsal raphe nucleus, where galanin coexists with serotonin. Furthermore, a galanin receptor antagonist, M40, attenuated the antidepressant-like effect of FLX in the forced swim test, a rodent preclinical screen commonly used to evaluate antidepressant-like efficacy. Direct activation of galanin receptors by a galanin receptor agonist, galnon, was found to produce an antidepressant-like effect in the same task. Two other antidepressant treatments also affected the galaninergic system in the monoaminergic nuclei: Electroconvulsive shock elevated galanin mRNA levels in dorsal raphe nucleus, whereas sleep deprivation increased galanin mRNA levels in the locus coeruleus, further underlining the connection between activation of the galaninergic system and antidepressant action of various clinically proven treatments.

https://www.pnas.org/content/pnas/102/3/874.full.pdf

A role for galanin in antidepressant actions with a focus on the dorsal raphe nucleus

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Steiger A (Max Planck Institute of Psychiatry, Munich, Germany). Sleep and endocrinology (Minisymposium). J Intern Med 2003; 254: 13–22.



A bidirectional interaction between sleep electroencephalogram and endocrine activity is well established in various species including humans. Various hormones (peptides and steroids) participate in sleep regulation. A keyrole was shown for the reciprocal interaction between sleep-promoting growth hormone-releasing hormone (GHRH) and sleep-impairing corticotropin-releasing hormone (CRH). Changes in the GHRH : CRH ratio result in changes of sleep-endocrine activity. It is thought that the change of this ratio in favour of CRH contributes to aberrances of sleep during ageing and depression (shallow sleep, blunted GH and elevated cortisol). Besides GHRH, ghrelin and galanin enhance slow wave sleep. Somatostatin is another sleep-impairing factor. Neuropeptide Y acts as a CRH antagonist and induces sleep onset. There are hints that CRH promotes rapid eye movement sleep (REMS). In animals prolactin enhances REMS. In humans vasocactive intestinal polypeptide (VIP) appears to play a role in the temporal organization of sleep as, after VIP, the non-REMS–REMS cycle decelerated. Cortisol appears to enhance REMS. Finally, gonadal hormones participate in sleep regulation. Oestrogen replacement therapy and CRH-1 receptor antagonism in depression are beneficial clinical applications of sleep-endocrine research.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1365-2796.2003.01175.x

Sleep and endocrinology

Galanin is a highly inducible neuropeptide, showing distinct up-regulation after pathological disturbance within the nervous system. Significant increase in galanin expression is observed after peripheral nerve injury, in the basal forebrain in Alzheimer’s disease (AD), during neuronal development, and after stimulation with estrogen, while seizure activity deplete galanin in the hippocampus. A wide distribution of galanin and its receptors is seen in the nervous system, often in co-localization with classical neurotransmitters and other neuromodulators. Galanin acts predominantly as an inhibitory, hyperpolarizing neuromodulator on neurotransmitter and glucose-induced insulin release and stimulates growth hormone and prolactin secretion. Galanin has been implicated in several higher order physiological functions including cognition, feeding, nociception, mood regulation, and neuroendocrine modulation. The effects of galanin are mediated via three G protein-coupled receptors with different functional coupling. Moderate to low pharmacological effects are seen by galanin under physiological conditions, in contrast to its dramatic effects on the nervous system after neuronal disturbance. This pathophysiological heavy function of the galaninergic system renders it an interest for disorders such as AD, depression, and epilepsy in terms of side effects. Some properties of the galaninergic system are of particular importance in the context of neurodegeneration. Galanin is highly inducible, 10- to 100-fold, upon nerve injury, whereas most neuropeptides are induced 1.5- to 2-fold. Galanin is strongly neurotrophic during development as well as subsequent to injury. Whereas other neurotrophic neuropeptides like VIP and PACAP activate cAMP synthesis, galanin suppresses its synthesis, yet it is a strong neurotrophic as well as neuroprotective agent. As we delineate which galanin receptor subtype mediates neuroprotective and neurotrophic effects and which mediates synaptic inhibition, pharmacological use of receptor-selective galaninergic ligands for treatment in neurodegenerative diseases are coming closer.

Galanin and its receptors in neurological disorders.

Galanin has REM-sleep deprivation-like effects on the sleep EEG in healthy young men.

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Galanin has REM-sleep deprivation-like effects on the sleep EEG in healthy young men.