Increased serotonin receptor availability in human sleep: Evidence from an [18F]MPPF PET study in narcolepsy

Data from animal studies suggest that serotonin release promotes wakefulness and suppresses REM sleep, but there are dangers in extrapolating these findings to humans. Binding of the radioligand [18F]MPPF to 5HT1A receptors is sensitive to levels of endogenous serotonin. In this study, we aimed to demonstrate changes in serotonin receptor availability in the human brain in wakefulness and sleep using [18F]MPPF and positron emission tomography. 14 subjects with narcolepsy cataplexy underwent [18F]MPPF PET scans in wakefulness and in sleep. Subjects who used the stimulant methylphenidate took their normal medication for the wake scan but omitted it prior to the sleep scan. The change in binding potential (BP) between the sleep and wake scans was examined using paired t test. Methylphenidate is thought to have little or no effect on serotonergic neurotransmission, and in order to confirm the absence of an effect on [18F]MPPF binding, a concurrent study was performed using a beta-microprobe technique to examine the effect of methylphenidate administration on [18F]MPPF binding in Sprague-Dawley rats. The human study showed a significant increase in [18F]MPPF binding in sleep compared to wakefulness in the whole brain and all regions of interest examined (temporal cortex, mesial temporal region and cingulate cortex). The beta-microprobe study confirmed that methylphenidate administration had no effect on [18F]MPPF binding. These findings indicate that serotonin receptor availability is increased in sleep compared to wakefulness in narcoleptic humans.

[1]  F. Sakai,et al.  Normal human sleep: Regional cerebral hemodynamics , 1980, Annals of neurology.

[2]  H. Meltzer,et al.  Serotonin1A receptors are increased in postmortem prefrontal cortex in schizophrenia , 1996, Brain Research.

[3]  D. Segal,et al.  Escalating dose-binge stimulant exposure: relationship between emergent behavioral profile and differential caudate-putamen and nucleus accumbens dopamine responses , 1999, Psychopharmacology.

[4]  A. N. van den Pol,et al.  Hypocretins (Orexins) Regulate Serotonin Neurons in the Dorsal Raphe Nucleus by Excitatory Direct and Inhibitory Indirect Actions , 2002, The Journal of Neuroscience.

[5]  André Luxen,et al.  Effect of endogenous serotonin on the binding of the 5‐HT1A PET ligand 18F‐MPPF in the rat hippocampus: kinetic β measurements combined with microdialysis , 2002, Journal of neurochemistry.

[6]  S. Greenfield,et al.  Comparison of Serotonin and Dopamine Release in Substantia Nigra and Ventral Tegmental Area: Region and Species Differences , 1997, Journal of neurochemistry.

[7]  Barry L. Jacobs,et al.  Raphe unit activity in freely moving cats: Correlation with level of behavioral arousal , 1979, Brain Research.

[8]  Jan Pruim,et al.  5‐HT1A receptor imaging in the human brain: Effect of tryptophan depletion and infusion on [18F]MPPF binding , 2002 .

[9]  B. Bjorvatn,et al.  On-line detection of extracellular levels of serotonin in dorsal raphe nucleus and frontal cortex over the sleep/wake cycle in the freely moving rat , 1998, Neuroscience.

[10]  A. Meneses,et al.  5-HT system and cognition , 1999, Neuroscience & Biobehavioral Reviews.

[11]  D. Brooks,et al.  Evidence for striatal dopamine release during a video game , 1998, Nature.

[12]  C. Wilson,et al.  Ultradian sleep-cycle variation of serotonin in the human lateral ventricle , 2002, Neurology.

[13]  A. Bouhuys,et al.  Effects of midbrain raphe destruction on sleep and locomotor activity in rats , 1977, Physiology & Behavior.

[14]  Alan C. Evans,et al.  Regional Cerebral Blood Flow Changes as a Function of Delta and Spindle Activity during Slow Wave Sleep in Humans , 1997, The Journal of Neuroscience.

[15]  J. Engel,et al.  In vivo microdialysis measures of extracellular serotonin in the rat hippocampus during sleep–wakefulness , 1999, Brain Research.

[16]  D. Segal,et al.  Effects of Methylphenidate on Extracellular Dopamine, Serotonin, and Norepinephrine: Comparison with Amphetamine , 1997, Journal of neurochemistry.

[17]  A. Rechtschaffen,et al.  A manual of standardized terminology, technique and scoring system for sleep stages of human subjects , 1968 .

[18]  D Comar,et al.  High-yield radiosynthesis and preliminary in vivo evaluation of p-[18F]MPPF, a fluoro analog of WAY-100635. , 1998, Nuclear medicine and biology.

[19]  R. McCarley,et al.  Behavioral state-related changes of extracellular serotonin concentration in the dorsal raphe nucleus: a microdialysis study in the freely moving cat , 1994, Brain Research.

[20]  H. Kung,et al.  Derivatives of 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl-p-iodobenzamido)ethyl]pipera zine (p-MPPI) as 5-HT1A ligands. , 1994, Journal of medicinal chemistry.

[21]  G. E. Pickard,et al.  Response of the Mouse Circadian System to Serotonin 1A/2/7 Agonists in vivo: Surprisingly Little , 2003, Journal of biological rhythms.

[22]  R. Godbout,et al.  Nocturnal sleep of narcoleptic patients: revisited. , 1986, Sleep.

[23]  Latifa Rbah,et al.  Displacement of the PET ligand 18F‐MPPF by the electrically evoked serotonin release in the rat hippocampus , 2003, Synapse.

[24]  M. Laruelle.  Imaging Synaptic Neurotransmission with in Vivo Binding Competition Techniques: A Critical Review , 2000, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[25]  J. Glowinski,et al.  In vivo release of 5-HT in the lateral ventricle of the rat: effects of 5-hydroxytryptophan and tryptophan , 1976, Brain Research.

[26]  Latifa Rbah,et al.  A reduced extracellular serotonin level increases the 5-HT1A PET ligand 18F-MPPF binding in the rat hippocampus. , 2003, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[27]  J. O. Schenk.  The functioning neuronal transporter for dopamine: kinetic mechanisms and effects of amphetamines, cocaine and methylphenidate. , 2002, Progress in drug research. Fortschritte der Arzneimittelforschung. Progres des recherches pharmaceutiques.

[28]  Sebastiaan Overeem,et al.  Hypocretin (orexin) deficiency in human narcolepsy , 2000, The Lancet.

[29]  M. Jouvet,et al.  The role of monoamines and acetylcholine-containing neurons in the regulation of the sleep-waking cycle. , 1972, Ergebnisse der Physiologie, biologischen Chemie und experimentellen Pharmakologie.

[30]  P. Celada,et al.  The therapeutic role of 5-HT1A and 5-HT2A receptors in depression. , 2004, Journal of psychiatry & neuroscience : JPN.

[31]  R. McCarley,et al.  Behavioral state-related changes of extracellular serotonin concentration in the pedunculopontine tegmental nucleus: a microdialysis study in freely moving animals. , 1999, Sleep research online : SRO.

[32]  Laurent Descarries,et al.  Acute Treatment with the Antidepressant Fluoxetine Internalizes 5-HT1A Autoreceptors and Reduces the In Vivo Binding of the PET Radioligand [18F]MPPF in the Nucleus Raphe Dorsalis of Rat , 2004, The Journal of Neuroscience.

[33]  A. Lammertsma,et al.  Simplified Reference Tissue Model for PET Receptor Studies , 1996, NeuroImage.

[34]  A. Braun,et al.  Regional cerebral blood flow throughout the sleep-wake cycle. An H2(15)O PET study. , 1997, Brain : a journal of neurology.

[35]  T Suhara,et al.  In vivo binding properties of [carbonyl‐11C]WAY‐100635: Effect of endogenous serotonin , 2001, Synapse.

[36]  A. Rechtschaffen.  A manual of standardized terminology, techniques and scoring system for sleep of human subjects , 1968 .

[37]  C. McDougle,et al.  Tryptophan Depletion During Continuous CSF Sampling in Healthy Human Subjects , 1998, Neuropsychopharmacology.

[38]  B. Hoebel,et al.  Microdialysis Studies of Brain Norepinephrine, Serotonin, and Dopamine Release During Ingestive Behavior Theoretical and Clinical Implications a , 1989, Annals of the New York Academy of Sciences.

[39]  H. Haas,et al.  Convergent Excitation of Dorsal Raphe Serotonin Neurons by Multiple Arousal Systems (Orexin/Hypocretin, Histamine and Noradrenaline) , 2002, The Journal of Neuroscience.

[40]  Paul Kinahan,et al.  Analytic 3D image reconstruction using all detected events , 1989 .

[41]  R. Broughton,et al.  Effects of Nocturnal Gamma-Hydroxybutyrate on Sleep/Waking Patterns in Narcolepsy-Cataplexy , 1980, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[42]  A. Frazer,et al.  Effects of novel 5-HT1A receptor antagonists on measures of post-synaptic 5-HT1A receptor activation in vivo. , 1995, Life sciences.

[43]  J. Mazziotta,et al.  Rapid Automated Algorithm for Aligning and Reslicing PET Images , 1992, Journal of computer assisted tomography.

[44]  M. Jouvet,et al.  Single unit recordings in the nuclei raphe dorsalis and magnus during the sleep-waking cycle of semi-chronic prepared cats , 1981, Neuroscience Letters.

[45]  H. Wikström,et al.  Autoradiographic localization of 5-HT1A receptors in the post-mortem human brain using [3H]WAY-100635 and [11C]WAY-100635 , 1997, Brain Research.

[46]  Paul J. Harrison,et al.  The distribution of 5-HT1A and 5-HT2A receptor mRNA in human brain , 1995, Brain Research.

[47]  Ronald M. Harper,et al.  Dorsal raphe neurons: depression of firing during sleep in cats , 1976, Brain Research.

[48]  W Vaalburg,et al.  On the quantification of [18F]MPPF binding to 5-HT1A receptors in the human brain. , 2001, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[49]  E. Mignot,et al.  On the value of measuring CSF hypocretin-1 in diagnosing narcolepsy. , 2003, Sleep.