Locus Coeruleus-Pineal Melatonin Interactions and the Pathogenesis of the “On-Off” Phenomenon Associated with Mood Changes and Sensory Symptoms in Parkinson's Disease

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Abstract
The "on-off" phenomenon has been reported to occur in more than 50% of patients with Parkinson's disease after 5 years of treatment with levodopa. Several recent studies have reported an association between the "on-off" phenomenon, concurrent mood changes and sensory symptoms in patients with Parkinson's disease. In these reports, "off" was associated with exacerbation of depression, anxiety and sensory symptoms, while "on" was accompanied by normalization of mood with occasional elation and attenuation in the severity of the sensory symptoms. These observations suggest that the biological mechanisms of the "on-off" interact with mechanisms regulating mood and sensory functions. The "on-off" phenomenon may be related to primary degenerative changes in the locus coeruleus (LC). The emergence of mood changes and sensory symptoms associated with the "on-off" may be facilitated by deregulation of LC-pineal melatonin functions. Administration of noradrenergic agents may be beneficial in attenuating the severity of the motor dyskinesias of the "on-off" while serotonergic drugs alone or in combination with melatonin-release enhancing agents may be useful in the management of the mood changes and sensory symptoms.