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Dornbierer, Dario
Zeilhofer, Hanns-Ulrich
Quitterer, Ursula
Landolt, Hans-Peter
Quednow, Boris B.
Neuropsychiatric disorders represent a major health care challenge of the 21st century. Despite the high prevalence of these disorders, most of the currently available psychopharmacological therapies show suboptimal efficacy. Thus, there is an urgent need for novel, effective and sustainable psychiatric treatments. Unfortunately, major pharmaceutical companies have abandoned neuropsychiatric research due to the high risk of failure associated with the particular complexity of psychopharmacological drug development. Thus, drug repurposing has gained substantial interest in research areas of high failure risk, such as psychiatry. Drug repurposing means to discover new therapeutic aspects of an existing or abandoned drug, with the goal of expanding the drug’s therapeutic indications. A promising repurposing candidate, which is under current investigation for the treatment of several neuropsychiatric disorders, is gamma-hydroxybutyrate (GHB), also known as liquid ecstasy, k.o. drops or date-rape drug. GHB is an endogenous GABAB/GHB receptor agonist that occurs naturally in the mammalian brain. Due to its stimulating, euphorogenic and prosexual effects it is abused recreationally. Beyond that, GHB is approved for the treatment of alcohol withdrawal syndrome and narcolepsy with cataplexy. The latter condition is characterized by severe sleep disturbances, excessive daytime sleepiness and cataplexy. Intriguingly, nocturnal administration of GHB has proven potency to reduce excessive daytime sleepiness and the number of cataplectic episodes in narcolepsy patients. Likewise, GHB has been effective in ameliorating sleep and waking quality in Parkinson’s disease and fibromyalgia. Given the high prevalence of impaired sleep quality in neuropsychiatric diseases, GHB has become a promising candidate to treat sleep disturbances and insomnia-related symptoms in these disorders. Despite GHB’s therapeutic potential, little is known about its underlying mechanisms of action. Thus, in the current thesis, I explored the effects of nocturnal GHB administration on biological functions that are frequently impaired in neuropsychiatric patients, namely: sleep neurophysiology (chapter 2), neuro-immune interactions (chapter 3) and brain metabolism (chapter 4). To this end, GHB (50 mg/kg body weight) and placebo were administered in 20 young male volunteers at 2:30 am, in the middle of a sleep episode, the time when GHB is typically given in narcolepsy. The sleep study followed a randomized, double-blinded, balanced, cross- over design. In chapter 2, a detailed neurophysiological assessment of GHB’s sleep promoting effects was conducted, by analyzing the drug effects on sleep architecture, regional changes in electroencephalographic (EEG) sleep spectra, brain electrical sources, and lagged phase synchronization. GHB prolonged slow wave sleep (stage N3) at the cost of rapid-eye-movement (REM) sleep. Furthermore, it enhanced delta- theta (0.5-8 Hz) activity in non-rapid-eye-movement (NREM) and REM sleep, while reducing activity in the spindle frequency range (13-15 Hz) in sleep stage N2. The increase in delta power predominated in medial prefrontal cortex, parahippocampal and fusiform gyri, and posterior cingulate cortex. Theta power was particularly increased in the prefrontal cortex and both temporal poles. Finally, the brain areas which were significantly affected by GHB, also exhibited increased lagged phase synchronization in the theta range among each other. This detailed neurophysiological analysis revealed distinct similarities between GHB-augmented sleep and physiologically augmented sleep as seen in recovery sleep after prolonged wakefulness. The promotion of the sleep neurophysiological mechanisms by GHB may, thus, provide a rationale for GHB-induced sleep and waking quality in neuropsychiatric disorders beyond narcolepsy. In chapter 3, effects of GHB on neuro-immune interactions were explored. More specifically, tryptophan catabolites (TRYCATs), brain derived neurotrophic factor (BDNF), the cortisol awakening response (CAR) and affective states (Positive and Negative Affect Schedule, PANAS) were measured in the morning, following nocturnal GHB or placebo administration. GHB reduced morning plasma levels of the TRYCATs, indolelactic acid, kynurenine, kynurenic acid, 3- hydroxykynurenine, and quinolinic acid, the 3-hydroxykynurenine to kynurenic acid ratio and the CAR. Serotonin, tryptophan, and BDNF levels, as well as PANAS scores in the morning remained unchanged after nocturnal GHB challenge. These findings indicate, that GHB may protect the brain against the detrimental impact of inflammation and chronic stress on neuronal functioning and mood. This action may explain some of GHB’s therapeutic effects in neuropsychiatric disorders involving neuro-immunological pathologies. In chapter 4, the effects of GHB on post-awakening brain metabolite levels in the anterior cingulate cortex (ACC) were assessed using J- resolved magnetic resonance spectroscopy (JPRESS-MRS). Moreover, psychomotor vigilance, executive functions and subjective sleepiness were assessed. The analyses revealed increased morning glutamate levels in the ACC in all subjects in the GHB condition compared to placebo. Moreover, GHB reduced median reaction times on the psychomotor vigilance task. Executive functions and subjective sleepiness remained unaffected by the drug. It is hypothesized that GHB may reduce glutamate release during its acute phase, causing a presynaptic glutamate accumulation and a subsequent rebound when acute drug effects fade away in the early morning. With that, GHB may exert protecting effects against excitoxicity, by suppressing glutamate release during the night. On the other hand, this acute suppression may restore glutamate storages for the subsequent day, giving account for GHB’s wake-promoting effects. In chapter 5, the acute effects of GHB (20 and 35 mg/kg) on behavioral and neurophysiological correlates of performance and conflict monitoring (PM and CM) were assessed in 15 healthy male volunteers, using the Eriksen-Flanker paradigm in a randomized, double-blind, placebo-controlled, balanced, cross-over study. PM and CM represent two essential cognitive abilities, required to appropriately respond to demanding tasks and can be investigated by means of event-related brain potentials (ERP) and associated neuronal oscillations. Thereby, the error-related negativity (ERN) represents a correlate of PM, whereas the N2 component reflects the process of CM. GHB prolonged reaction times, without affecting error rates or post-error slowing. Moreover, GHB decreased ERN amplitudes and associated neuronal oscillations in the theta/alpha1 range. Similarly, neuronal oscillations associated with the N2 were reduced in the theta/alpha1 range, but conversely the N2 amplitude was increased. Hence, GHB shows a dissociating effect on electrophysiological correlates of PM and CM, which is suggested to be mediated by an acute inhibition of the ACC. In summary, the current thesis suggests that GHB may owe its unique clinical potential to the remarkable ability to enhance physiological sleep functions in a biomimetic manner. This biomimetic sleep enhancement may reduce oxidative stress load by decreasing the concentration of free-radical producing metabolites, such as 3- hydroxykynurenin. Moreover, GHB may protect the brain against excitotoxicity, by suppressing glutamate release during the night and reducing plasma levels of the neurotoxic TRYCAT quinolinic acid. On the other hand, GHB may promote waking-quality by reducing sleep pressure, restock cerebral energy reserves and provide refilled glutamate storages for the next day. Each of these attributes may reflect GHB’s unique capacity to induce a regenerative state of metabolic arrest similar to that found in natural sleep.
ETH Zurich
Sleep pharmacology
Repurposing gamma-hydroxybutyrate for neuropsychiatric disorders? Examining its effects on sleep neurophysiology, neuro- immune interaction and brain metabolites in healthy men
Doctoral Thesis
In Copyright - Non-Commercial Use Permitted
228 p.
DDC - DDC::6 - Technology, medicine and applied sciences::610 - Medical sciences, medicine
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02020 - Dep. Chemie und Angewandte Biowiss. / Dep. of Chemistry and Applied Biosc.::02534 - Institut für Pharmazeutische Wiss. / Institute of Pharmaceutical Sciences::03742 - Zeilhofer, Hanns U. / Zeilhofer, Hanns U.
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