The Role of the Substantia Nigra Pars Compacta in Regulating Sleep Patterns in Rats

Abstract

BackgroundAs of late, dopaminergic neurotransmission has been recognized to be involved in the generation of sleep disturbances. Increasing evidence shows that sleep disturbances in Parkinson's disease (PD) patients are mostly related to the disease itself, rather than being a secondary phenomenon. Evidence contained in the literature lends support to the hypothesis that the dopaminergic nigrostriatal pathway is closely involved in the regulation of sleep patterns.Methodology/Principal FindingsTo test this hypothesis we examined the electrophysiological activity along the sleep-wake cycle of rats submitted to a surgically induced lesion of the SNpc by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We demonstrated that a 50% lesion of the substantia nigra pars compacta (SNpc) suffices to produce disruptions of several parameters in the sleep-wake pattern of rats. A robust and constant decrease in the latency to the onset of slow wave sleep (SWS) was detected throughout the five days of recording in both light [F(22.16) = 72.46, p<0.0001] and dark [F(22.16) = 75.0, p<0.0001] periods. Also found was a pronounced increase in the percentage of sleep efficiency during the first four days of recording [F(21.15) = 21.48, p<0.0001], in comparison to the sham group. Additionally, the reduction in the SNpc dopaminergic neurons provoked an ablation in the percentage of rapid eye movement sleep (REM) during three days of the sleep-wake recording period with a strong correlation (r = 0.91; p<0.0001) between the number of dopaminergic neurons lost and the percentage decrease of REM sleep on the first day of recording. On day 4, the percentage of REM sleep during the light and dark periods was increased, [F(22.16) = 2.46, p<0.0007], a phenomenon consistent with REM rebound.Conclusions/SignificanceWe propose that dopaminergic neurons present in the SNpc possess a fundamental function in the regulation of sleep processes, particularly in promoting REM sleep.

Intranigral LPS Administration Produces Dopamine, Glutathione but not Behavioral Impairment in Comparison to MPTP and 6-OHDA Neurotoxin Models of Parkinson’s Disease

“…Accordingly, the neurochemical profile promoted by LPS was comparable to that elicited by MPTP, which is considered a toxin that generates a mild neurodegeneration, even in a repeated intranigral administration protocol [12]. Hence, it is postulated that MPTP particularly model the early phase of PD, which is primarily characterized by the occurrence of cognitive, emotional and sleep deficits, than motor abnormalities [6,8,10,14,21,35]. The neuronal degeneration promoted by 6-OHDA is characteristically more evident at seven days after the neurotoxin administration, however some markers (e.g.…”

“…In addition, loss of tyrosine hydroxylase immunoreactivity (TH-ir) began in axons at 6 h, and progressed to cell bodies at later time-points post lesion [36]. Similarly, MPTP can cause a short term dopaminergic neurodegeneration with reductions of nigral TH expression as well as TH-ir cell death [4,8,12]. Moreover, a single injection of LPS to the SNpc region of Wistar, Fisher or Sprague-Dawley rats indeed leads to a fast marked loss (50-85%) of SNpc dopaminergic neurons [1,38].…”

“…Some models of PD are achieved by the use of neurotoxins, in particular 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA), and recently the endotoxin found in the outer membrane of gram-negative bacteria, lipopolysaccharide (LPS) [1][2][3]. In most of the studies of PD models, several of the motor, cognitive, affective, neurochemical, inflammatory and sleep disruptions encountered in the human disease are partially recapitulated by MPTP, 6-OHDA and LPS [4][5][6][7][8][9][10][11][12][13][14].…”

Increased Motor Activity During REM Sleep Is Linked with Dopamine Function in Idiopathic REM Sleep Behavior Disorder and Parkinson Disease

“…23,33 Furthermore, Takakusaki et al showed that the excessive GABAergic output from the basal ganglia to the PPN in patients with PD may induce sleep disturbances, including a reduction of REM sleep periods and REM sleep behavioral disorders as REM without atonia. 5 Studies in MPTP-treated rats, cats, and monkeys have also reported a role for dopaminergic neurons in the substantia nigra in the regulation of REM sleep, 3,4,34,35 In addition, dopamine D2-receptor immunoreactivity has been found in brainstem structures involved in REM M Zoetmulder, M Nikolic, H Biernat et al Increased EMG-activity is linked to Dopamine in iRBD and PD sleep without atonia, including subcoeruleus, lateral paragigantocellular, nucleus raphe magnus, gigantocellular nucleus pars alpha, ventral gigantocellular nucleus, and raphe obscurus. 33,36 We found significant inverse correlations between 123 I-FP-CIT uptake and non-periodic EMG activity in the mentalis and tibialis muscle in PD patients with RBD during NREM sleep.…”

“…It is increasingly recognized that the dopaminergic system is associated with sleep-wake disturbances. 3,4 Previous studies have shown that basal ganglia structures, such as the substantia nigra pars reticulata and the internal segment of the globus pallidus, have caudal connections to regions that modulate REM sleep atonia. 5 Imaging studies in iRBD patients have shown microstructural changes in substantia nigra, 6 reduced volume of the putamen, 7 as well as reduced density of the striatal dopamine transporter, which decreases in the course of disease progression.…”