Many years of research have demonstrated the ability of the hypothalamus to control the homeostatic state and physiology in animals. Specific lesions experiments have characterized sub-nuclei of the hypothalamus that are important in sleep, feeding, autonomic control, sex drive and motivational behavior. The hypocretin neurons that are located in the dorso-lateral hypothalamus provide a dense innervation to the other nuclei within the hypothalamus as well as the monoaminergic systems, in particular key areas for behavior control. Hypocretins are involved in several hypothalamic functions as control of vigilance state, feeding and energy balance but also other as neuroendocrine system function.
Because of the recent interest in hypocretin dysfunction in neurological diseases and because of the functions of the hcrts, recent studies have evaluated whether altered hypocretin neurotransmission might be also involved in some psychiatric disorders. We will focus in the present review on depression and schizophrenia. The involvement of the hypocretins in stress and drug addiction is also today documented and we recommend to the readers to refer to the specific chapters in the book devoted to these two aspects of behavior. The hcrt system is also currently evaluated in other psychiatric disorders such as eating disorders.
Sleep disturbances are common and early symptoms in depression. The relationship between depression, sleep and circadian rhythms has been strongly documented. In some cases insomnia, stress and depression are even seen as continuum and a significant number of narcoleptic patients suffer from depression. Depression is associated with short REM sleep latencies in many cases. REM sleep is suppressed by almost all antidepressant medications and sleep deprivation. REM sleep deprivation has antidepressant effect. The neurochemistry of depression has focused on monoaminergic dysfunction, especially noradrenergic and serotoninergic pathways. The hypocretins, two neuropeptides that promote wakefulness and inhibit REM sleep are upregulated under REM sleep deprivation45 and might be involved in his antidepressant effect. In addition, the projections distribution of the hypocretins is coherent with a direct involvement in depression since these projections are noted in aminergic cell groups i.e. the noradrenergic locus coeruleus, the serotoninergic dorsal raphe, the histaminergic tuberomamillary nucleus and the dopaminergic substantia nigra and ventral tegmental area, and also cholinergic groups with a neuroexcitatory effect.46 Finally, hypocretins enhance the monoaminergic tone,35,47 as the antidepressant agents, and also activate the hypothalamic-pituitary-adrenal-axis whose changes in diurnal activity are observed in depression.
In animals, the Wistar-Kyoto (WKY) rats have increased REM sleep from early in development and are hypoactive, hypophagic and less sensitive to antidepressant drugs leading to the use of this model as a model of depression. Even considering the intrinsic restrictions of an animal model of depression as compared to the complexity of a depressive syndrome, it is interesting to notice that this latter model has a brain hypocretin deficiency especially observed in control areas of sleep and emotion.48
In human, the group headed by E. Mignot examined hypocretin-1 levels in the CSF of 14 control and 15 depressed patients.49 The mean baseline values in control subjects were not different from patients indicating that hypocretin deficiency is an unlikely cause for depression. They also explored whether antidepressant treatment modified hypocretin-1 levels in depressed subjects. They found that treatment with sertraline but not bupropion, was associated with decreased hypocretin levels, suggesting a small serotoninergic influence of the 5-HT system on the hypocretinergic tone which is supported by anatomical data showing tight contacts between serotoninergic fibers and hypocretin-containing cells. More interestingly, they observed a small slight but significant reduction in the amplitude of circadian rhythm of hypocretin-1 levels in depressed subjects as compared to controls. Surprisingly, the diurnal variation in hypocretin-1 levels was the opposite of that observed in rats and monkeys and the circadian variation was low which may be partialy explained by the fact that CSF was drawn continuously in supine subjects who were confined to bed rest.49 Diminished circadian rhythms of behaviors, physiologic measures and peripheral neuroendocrine functions can be observed in depression50 and circadian hypocretin variation might be one of the reduced oscillating parameter. Even if a slight improvement of the amplitude was observed in treated patients, it is impossible to conclude today because of the small sample size. It needs to be replicate and more interestingly in different subtypes of depression. Indeed, depression includes different depressive syndromes whose physiopathology is probably different even if sharing some common biological mechanisms. Under this light, it would be of great interest to study the hypocretin circadian variation in seasonal affective disorder, a subtype of depression with chronobiological abnormalities. Anatomical and physiological data support this hypothesis since hypocretins neurons are indirectly under the control of the central circadian pacemaker, the suprachiasmatic nucleus, via a relay in the dorsomedial hypothalamus and the lesion of the SCN eliminate the daily rhythm of hypocretin-1 release.51 It would be also interesting to examine the level of expression of hypocretin in mania.
CSF hypocretin levels have also been studied in a psychotic disorder, schizophrenia. The hypocretins have been shown to have a neuroexcitatory effect on the midbrain dopaminergic neurons. Central administration of hypocretins increases the number of stereotypy as well as locomotor activity, an effect that is prevented by the administration of dopaminergic D2 receptor antagonists, a class of compounds used in the treatment of schizophrenia.52 Hypocretin has also been shown to activate the hypothalamo- pituitary adrenal axis leading to an increase in release of corticotropin releasing hormone (CRH).53,54 Because abnormalities of the HPA axis and especially of the dopaminergic transmission are reported in schizophrenia and because sleep abnormalities are commonly observed in schizophrenic patients, Nishino and colleagues examined the hypocretin-1 levels in the CSF of 13 patients and 12 controls.55 Hypocretin dysfunction is unlikely to be involved or to mediate dopaminergic dysfunction observed in schizophrenia since CSF hypocretin levels were similar in the two groups. The only significant result reported by the authors was a positive correlation in schizophrenic patients, but not in control subjects, of the hypocretin levels with sleep latency, one of the most consistent sleep disturbances observed in schizophrenia. Dalal et al., evaluated the effect of antipsychotic drugs on the hcrt levels and they reported lower hcrt levels in patients treated with an haloperidol (antidopaminergic).56 All these results suggest that complementary experiments are necessary on a larger population of patients and controls, even if an altered hypocretin neurotransmission do not seem consistently to be involved in the pathophysiology of schizophrenia.
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