Dopamine (DA) is a neurotransmitter that modulates diverse waking behaviors including movement, motivation, cognition, reward, and feeding. Less appreciated and understood are dopamine's influences upon normal and pathologic sleep. Dopamine cell death which occurs in Parkinson's disease, is associated with profound alterations in wake-sleep state that can be broadly classified into disturbances of noctural movement and thalamocortical rhythmicity. The former include periodic leg movements of sleep and rapid-eye-movement sleep (REM-sleep) behavior disorder, while the later encompass loss of sleep spindles and slow-wave sleep, daytime sleepiness, and daytime intrusion of REM-sleep manifesting as hallucinatory behavior. Heuristic models of disease have limited themselves largely to DA's indirect, rather than direct actions upon thalamocortical circuits, and also to DA's participation in waking behaviors rather than thalamocortical arousal state (e.g., sleep). We have recently described a novel mesothalamic dopamine pathway originating via axon collaterals of the nigrostriatal pathway and which degenerates in PD. Mesencephalic dopamine neurons therefore have potential to modulate normal and pathologic behavior, including sleep, not only through traditional nigrostriatal pathways, but also by way of axon collaterals to the thalamus. Here we propose to define anatomical and physiological features of these novel circuits in non-human primates. S.A. number 1 employs microscopic techniques to establish the distribution, subcellular targets, topography, and collateralization of DA innervation in """"""""motor"""""""", """"""""prefrontal"""""""", """"""""limbic"""""""" and the reticular (i.e., the thalamic pacemaker) thalamic nuclei. S.A. number 2 will extend our preliminary electrophysiological demonstration of DA modulation of thalamic neural activity, by characterizing the responsivity of the same nuclei to focal dopaminomimetics. S.A.number 3 examines the state-related firing of midbrain DA neurons identified on the basis of their thalamic targets, and the state-related release of DA from functionally homologous striatal regions. These studies are a prerequisite to advancing our understanding of the pathophysiology and treatment of arousal disorders that accompany an array of neuropsychiatric conditions, particularly those which can be broadly defined as hyper- (e.g., schizophrenia) and hypodopaminergic (e.g., PD and restless legs/periodic leg movements of sleep).
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| Rye, David B (2004) Parkinson's disease and RLS: the dopaminergic bridge. Sleep Med 5:317-28 |
| Rye, David B (2004) The two faces of Eve: dopamine's modulation of wakefulness and sleep. Neurology 63:S2-7 |
| Keating, Glenda L; Rye, David B (2003) Where you least expect it: dopamine in the pons and modulation of sleep and REM-sleep. Sleep 26:788-9 |
