Gammahydroxybutyrate (GHB), a product of intermediary metabolism, has profound effects on the activity of the central nervous system (CNS), particularly on consciousness. Because of its soporific effects, GHB has become both a drug of abuse and, paradoxically, a clinically useful therapeutic for treatment of the sleep disorder narcolepsy. Narcolepsy, a Rapid Eye Movement (REM) sleep-related disorder that afflicts approximately 1 in 1000 Americans, is characterized by excessive daytime sleepiness (EDS), cataplexy (a sudden loss of muscle tone triggered by emotional stimulation), and a cluster of other symptoms. Xyrem, the sodium salt of GHB, has been approved by the U.S. Food and Drug Administration for the treatment of both the cataplexy and EDS symptoms of narcolepsy. GHB facilitates slow wave activity (SWA) in the EEG and slow wave sleep (SWS), thereby consolidating nocturnal sleep and resulting in increased alertness on the subsequent day. Despite its clinical utility, the mechanism of action of GHB remains controversial with evidence for action both through GABA-B receptors and through specific GHB binding sites in the CNS. The specific goals of this project are to identify the neural substrates of GHB-induced SWA and understand the mechanism(s) underlying the therapeutic effects of GHB on narcolepsy/cataplexy. To achieve these goals, we will exploit a mouse model of narcolepsy/cataplexy in which the hypocretin (Hcrt) neurons degenerate postnatally as they do in human narcoleptics. We will follow up on our preliminary results using these hcrt/ataxin-3 mice which indicate that GHB can reduce cataplexy-like symptoms as it does in humans and test the hypothesis that these therapeutic effects are mediated through the GABA-B receptor. We will conduct functional neuroanatomical studies to test the hypothesis that GHB differentially affects behavioral state regulatory regions in hcrt/ataxin-3 mice. Based on our preliminary results in which GHB induces Fos expression in the locus coeruleus (LC), we will use the neurotoxin DSP-4 to lesion noradrenergic cells to test the hypothesis that an intact LC is necessary for the therapeutic effect of GHB. We will also conduct cellular electrophysiological studies to determine whether the intrinsic properties of the neurons in the LC or the ventrolateral preoptic area (VLPO) are affected by acute or chronic exposure to GHB. Lastly, we will evaluate whether the therapeutic efficacy of GHB is associated with brain gene expression changes. The results of the studies proposed above will enhance our understanding of the neurobiology that underlies the therapeutic activity of GHB and may also provide insights into the cellular and molecular mechanisms that underlie cataplexy and EEG SWA.

Public Health Relevance

In patients with narcolepsy, a sleep disorder characterized by excessive daytime sleepiness and related symptoms, degeneration of hypocretin (Hcrt) neurons in the brain has been observed. Gammahydroxybutyrate (GHB) is a clinically useful therapeutic for treatment of the sleep disorder narcolepsy but the mechanism of action is unknown. We will exploit a mouse model of narcolepsy in which the Hcrt neurons degenerate postnatally as they do in human narcoleptics to understand how GHB is beneficial in human narcolepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS057464-01A2S2
Application #
7871825
Study Section
Biological Rhythms and Sleep Study Section (BRS)
Program Officer
Mitler, Merrill
Project Start
2008-09-05
Project End
2009-11-30
Budget Start
2009-09-01
Budget End
2009-11-30
Support Year
1
Fiscal Year
2009
Total Cost
$91,100
Indirect Cost
Name
Sri International
Department
Type
DUNS #
009232752
City
Menlo Park
State
CA
Country
United States
Zip Code
94025
Fisher, Simon P; Schwartz, Michael D; Wurts-Black, Sarah et al. (2016) Quantitative Electroencephalographic Analysis Provides an Early-Stage Indicator of Disease Onset and Progression in the zQ175 Knock-In Mouse Model of Huntington's Disease. Sleep 39:379-91
Tabuchi, Sawako; Tsunematsu, Tomomi; Black, Sarah W et al. (2014) Conditional ablation of orexin/hypocretin neurons: a new mouse model for the study of narcolepsy and orexin system function. J Neurosci 34:6495-509
Black, Sarah Wurts; Morairty, Stephen R; Chen, Tsui-Ming et al. (2014) GABAB agonism promotes sleep and reduces cataplexy in murine narcolepsy. J Neurosci 34:6485-94
Black, Sarah Wurts; Morairty, Stephen R; Fisher, Simon P et al. (2013) Almorexant promotes sleep and exacerbates cataplexy in a murine model of narcolepsy. Sleep 36:325-36
Bittman, Eric L; Kilduff, Thomas S; Kriegsfeld, Lance J et al. (2013) Animal care practices in experiments on biological rhythms and sleep: report of the Joint Task Force of the Society for Research on Biological Rhythms and the Sleep Research Society. J Am Assoc Lab Anim Sci 52:437-43
Tabuchi, Sawako; Tsunematsu, Tomomi; Kilduff, Thomas S et al. (2013) Influence of inhibitory serotonergic inputs to orexin/hypocretin neurons on the diurnal rhythm of sleep and wakefulness. Sleep 36:1391-404
Tsunematsu, Tomomi; Kilduff, Thomas S; Boyden, Edward S et al. (2011) Acute optogenetic silencing of orexin/hypocretin neurons induces slow-wave sleep in mice. J Neurosci 31:10529-39
Scammell, Thomas E; Willie, Jon T; Guilleminault, Christian et al. (2009) A consensus definition of cataplexy in mouse models of narcolepsy. Sleep 32:111-6