The pineal gland hormone melatonin may play a role in synchronization of rat circadian rhythms. Free-running activity rhythms of the rat were entrained by a daily melatonin injection, with entrainment occurring when the onset of activity coincided with the time of daily injections. When injections were stopped, activity rhythms became free-running again. Thus in pharmacological experiments, the time of day of melatonin administration is crucial.

Five intensities of artificial light were examined for the effect on nocturnal melatonin concentrations. Maximum suppression of melatonin following 1 hr of light at midnight was 71%, 67%, 44%, 38%, and 16% with intensities of 3,000, 1,000, 500, 350, and 200 lux (lx), respectively. In contrast to some previous reports, light of 1,000 lx intensity was sufficient to suppress melatonin to near daytime levels, and intensities down to 350 lx were shown to significantly suppress nocturnal melatonin levels below prelight values. On the basis of these data, it is suggested that when examining the melatonin sensitivity of patient groups (such as bipolar affective disorders) to artificial light, an appropriate light intensity should be established in each laboratory. Light of less intensity (e.g., 200-350 lx) may be more suitable to dichotomize patient groups from control subjects.

For the past 40 years the primary purpose of therapeutics for Parkinson's disease (PD) has been to replace deficient dopamine (DA) in the nigrostriatal dopamine (NSD) system. Even in the presence of limited efficacy, abundant side effects and impoverished quality of life, the involvement of other systems in the aetiology and treatment of this disorder has been sorely neglected and the excessive use of DA replacement therapy (DART) continues on a global basis. Recent scientific work suggests that the retina plays a major role in NSD function and intimates light therapy in the management of PD. After a thorough review of historical evidence supporting this contention, a retrospective, open-label study on 129 PD patients, whereby they were monitored for a period extending for a few months to eight years, was carried out. Primary motor and non-motor symptoms were monitored using an objectified global rating scale and timed motor tests that were assessed at regular intervals for the duration of the study. Thirty-one patients with other neurological disorders (OND) served as controls to determine whether any therapeutic effects seen with light were generalizable across other conditions. Patients were classified as compliant (COM), semi-compliant (SCOM), or early quit (EQUIT; prematurely discontinued treatment). EQUIT patients showed deterioration, while the COM group improved on most parameters. The SCOM patients were not as good as the COM group. The OND group showed significant improvement in depression and insomnia, but exposure to light did not improve motor function. The total drug burden of PD patients maintained on light was less with fewer side effects than SCOM or EQUIT groups. These results confirm the value of the strategic application of light therapy with controlled doses of DART in PD and warrants further controlled investigation. That the symptomatic improvement continued as long patients remained in the program suggests that exposure to light, under a strict daily regimen, combined with controlled DART, actively slows or arrests the progressive degenerative process underlying PD.

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Although pinealectomy has little influence on the circadian locomotor rhythms of laboratory rats, administration of the pineal hormone melatonin has profound effects. Evidence for this comes from studies in which pharmacological doses of melatonin are administered under conditions of external desynchronization, internal desynchronization, steady state light-dark conditions, and phase shifts of the zeitgeber. Taken together with recent findings on melatonin receptor concentration in the rat hypothalamus, particularly at the level of the suprachiasmatic nuclei, these results suggest that melatonin is a potent synchronizer of rat circadian rhythms and has a direct action on the circadian pacemaker. It is possible, therefore, that the natural role of endogenous melatonin is to act as an internal zeitgeber for the total circadian structure of mammals at the level of cell, tissue, organ, whole organism and interaction of that organism with environmental photoperiod changes.

Although pinealectomy has little effect on the generation of circadian rhythmicity by mammals, daily injections of the pineal hormone melatonin entrain free-running rats [30]. The present study was designed to determine if known components of mammalian circadian organization were necessary for melatonin entrainment. Rats received either lesions to the suprachiasmatic nuclei (SCN), sham-lesions or neurotoxic lesions to brain catecholamines or serotonin. They were then allowed to free-run in constant dim red light (DD) before each received daily injections of either 1 mg/kg melatonin or ethanol:saline vehicle for 90 days. They were allowed to free-run for 30 days afterwards. Rats which received sham-lesions or neurotoxic lesions entrained to melatonin injections but not to vehicle. Rats which received complete SCN lesions were unaffected by melatonin or vehicle. These data suggest that the behavioral effects of melatonin, like those on reproduction in seasonally breeding mammals, depend upon an intact circadian system and the SCN.

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