Circadian activity disorder

Melatonin [73-31-4] C 2H N202 (31) has marked effects on circadian rhythm (11). Novel ligands for melatonin receptors such as (32) (12), C2yH2gN202, have affinities in the range of 10 Af, and have potential use as therapeutic agents in the treatment of the sleep disorders associated with jet lag. Such agents may also be usehil in the treatment of seasonal affective disorder (SAD), the depression associated with the winter months. Histamine (see Histamine and histamine antagonists), adenosine (see Nucleic acids), and neuropeptides such as corticotropin-like intermediate lobe peptide (CLIP) and vasoactive intestinal polypeptide (VIP) have also been reported to have sedative—hypnotic activities (7). 

A role for the 5-HT7 receptor in the regulation of circadian rhythms has been implicated. As discussed above, 5-HT has been known for some time to induce phase shifts in behavioral circadian rhythms and modulate neuronal activity in the suprachiasmatic nucleus, the likely site of the mammalian circadian clock. The pharmacological characteristics of the effect of 5-HT on circadian rhythms are consistent with 5-HT7 receptor. Moreover, mRNA for the 5-HT7 receptor is found in the suprachiasmatic nucleus. There is also increasing evidence that the 5-HT7 receptor may play a role in psychiatric disorders. The regional distribution of 5-HT7 receptors in brain includes limbic areas and cortex. Atypical antipsychotics, such as clozapine and risperidone, and some antidepressants display high affinity for this receptor. In the periphery, 5-HT7 receptors havebeenshown to mediate relaxation of vascular smooth muscle. 

The results obtained with the model for the mammalian circadian clock provide cues for circadian-rhythm-related sleep disorders in humans [117]. Thus permanent phase shifts in LD conditions could account for (a) the familial advanced sleep phase syndrome (FASPS) associated with PER hypopho-sphorylation [118, 119] and (b) the delayed sleep phase syndrome, which is also related to PER [120]. People affected by FASPS fall asleep around 7 30 p.m. and awake around 4 30 a.m. The duration of sleep is thus normal, but the phase is advanced by several hours. Moreover, the autonomous period measured for circadian rhythms in constant conditions is shorter [121]. The model shows that a decrease in the activity of the kinase responsible for PER phosphorylation is indeed accompanied by a reduction of the circadian period in continuous darkness and by a phase advance upon entrainment of the rhythm by the LD cycle [114]. 

Poor Timing of Neurotransmission. The activity of some brain circuits, like the secretion of certain hormones, varies at certain times of the day. Called circadian rhythms, the timing of these rhythms may be disrupted in some illnesses. Examples include sleep disorders such as insomnia and narcolepsy, as well as other conditions such as nighttime binge-eating disorder. 

Furthermore, many of these neurotransmitters subserve or intimately interact with a number of neuroendocrine, circadian rhythm, and neurophysiological activities, which may be dysregulated in mood disorders. Genetic defects are quite likely the basis for such pathology. 

This disorder occurs when there is a mismatch between the normal rest—activity schedule for a person s environment and the person s circadian sleep— wake pattern. There are four subtypes ... 

There is emerging evidence that OSA may be a pro-inflammatory disorder with elevated circulating cytokines [60]. Abdominal visceral fat is a major reservoir of cytokines, and obesity is a leading risk factor for the presence of OSA [60], The mechanism(s) whereby pro-inflammatory cytokines are elevated in OSA is not fully elucidated, but may be related to the excessive sympathetic nervous system activation notable in OSA. Tumor necrosis factor (TNF)-a and interleukin (IL)-6 levels are elevated in OSA [61,62] and the circadian rhythm of TNF-a is disrupted in OSA [63]. IL-6 levels are higher again in OSA patients with systemic hypertension compared to normotensive apneics [60], IL-6 levels return to normal in OSA patients treated effectively with CPAP [64]. Other mediators of inflammation elevated in OSA include intercellular adhesion molecule-1 and C-reactive protein, the latter being synthesized primarily in hepatocytes in response to IL-6 [60], The presence of these and other pro-inflammatory cytokines may link to the increased prevalence of cardiovascular morbidity in OSA. 

Wirz-Justice A, Werth E, Savaskan E, Knoblauch V, Gasio PF, Muller-Spahn F. Haloperidol disrupts, clozapine reinstates the circadian rest-activity cycle in a patient with early-onset Alzheimer disease. Alzheimer Dis Assoc Disord 2000 14(4) 212-5. 

In humans, circadian rhythms governed by the SCN affect a large number of physiological functions, including the sleep-wake cycle and nutrition (Moore-Ede et al, 1982 Touitou Haus, 1992). Moreover, a variety of hormone levels (Van Cauter Aschoff, 1989) or enzyme activities display circadian patterns. Circadian rhythms, accordingly, play important roles in both health and disease (Moore-Ede, Czeisler Richardson, 1983). Clinical applications of circadian rhythm research include the use of light to treat maladaptation to night work (Czeisler et al, 1990), jet lag, or seasonal affective disorder (Lewy et al, 1987). 

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