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An Experiment and a Systematic Review of Histamine and Several Amino Acids Cathalijn H

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An Experiment and a Systematic Review of Histamine and Several Amino Acids Cathalijn H -2851$/2) Leenaars, CHC, et al. 2019 Sleep and Microdialysis: An Experiment and &,5&$',$15+<7+06 a Systematic Review of Histamine and Several Amino Acids. Journal of Circadian Rhythms, 17(1): 7, pp. 1–12. DOI: https://doi.org/10.5334/jcr.183 RESEARCH ARTICLE Sleep and Microdialysis: An Experiment and a Systematic Review of Histamine and Several Amino Acids Cathalijn H. C. Leenaars*,†,‡, W. H. Pim Drinkenburg§, Christ Nolten§, Maurice Dematteis‖, Ruud N. J. M. A. Joosten¶, Matthijs G. P. Feenstra¶ and Rob B. M. De Vries* Sleep seems essential to proper functioning of the prefrontal cortex (PFC). The role of different neurotransmitters has been studied, mainly the catecholamines and serotonin. Less attention has been paid to the amino acid transmitters and histamine. Here, we focus on the activity of these molecules in the PFC during sleep and sleep deprivation (SD). We determined extracellular concentrations of histamine and 8 amino acids in the medial PFC before, during and after SD. Additionally, we systematically reviewed the literature on studies reporting microdialysis measurements relating to sleep throughout the brain. In our experiment, median concentrations of glutamate were higher during SD than during baseline (p = 0.013) and higher during the dark-active than during the resting phase (p = 0.003). Glutamine was higher during post-SD recovery than during baseline (p = 0.010). For other compounds, no differences were observed between light and dark circadian phase, and between sleep deprivation, recovery and baseline. We retrieved 13 papers reporting on one or more of the molecules of interest during naturally occurring sleep, 2 during sleep deprivation and 2 during both. Only two studies targeted PFC. Histamine was low during sleep, but high during sleep deprivation and wakefulness, irrespective of brain area. Glu (k = 11) and GABA (k = 8) concentrations in different brain areas were reported to peak during sleep or wakefulness or to lack state-dependency. Aspartate, glycine, asparagine and taurine were less often studied (1-2 times), but peaked exclusively during sleep. Sleep deprivation increased glutamate and GABA exclusively in the cortex. Further studies are needed for drawing solid conclusions. Keywords: Amino acids; Proline; Microdialysis; Prefrontal cortex; Sleep; Systematic Review; Glutamate; Glutamine; Glycine; Aspartate; Asparagine; GABA; Histamine; Taurine; Proline Introduction logical mechanisms involved, extracellular concentrations Sleep seems necessary for prefrontal cortex of neurotransmitters have been studied. In contrast to (PFC)-dependent tasks. Prefrontal regions show promi- monoamines [6] and adenosine [7], other transmitters that nent deactivation during sleep [1] and sleep deprivation are important in sleep regulation [8] such as the amino [2]. Besides, prefrontal tasks such as attention, working acids and histamine (Hist) did not receive much attention. memory, temporal memory and behavioural inhibition Therefore we focus here on 1) Hist, a monoamine that is as are affected by sleep deprivation in humans [3], but also important as the other monoamines in the regulation of in animals, e.g. on tasks addressing working memory and sleep and wakefulness but is much less studied, and 2) excit- task switching [4, 5]. To learn more about the neurobio- atory (e.g. glutamate (Glu) and aspartate (Asp)) and inhibi- tory (e.g. GABA (gamma-aminobutyric acid), glycine (Gly) and taurine (Tau)) neurotransmitters and neuromodulators * SYRCLE, Radboud Institute for Health Sciences, Radboud University Medical Center, NL [9, 10]. † Department of Animals in Science and Society – Human-Animal Microdialysis is a convenient and elegant method to Relationship, Faculty of Veterinary Sciences, Utrecht University, study extracellular biochemistry over time. Extracellular NL concentrations present direct information on the activ- ‡ Institute for Laboratory Animal Science, Hannover Medical ity status of neurotransmitters and neuromodulators in School, DE a certain brain region, in contrast to total brain concen- § Janssen Research and Development, a division of Janssen trations [11]. Microdialysis is based on simple diffusion Pharmaceutica N.V., BE through a semi-permeable membrane; from the tissue ‖ Department of Addiction Medicine, Grenobles Alpes University of interest into a continuously flowing isotonic fluid. The Hospital and Grenoble Alpes University, FR dialysate is then analysed by ultra-high-pressure liquid ¶ Netherlands Institute for Neuroscience (NIN), An Institute of the Royal Netherlands Academy of Arts and Sciences, NL chromatography (UPLC). Corresponding author: Cathalijn H. C. Leenaars In this paper we describe our experiment that investi- ([email protected]) gates the effects of 12h of sleep deprivation on medial Art. 7, page 2 of 12 Leenaars et al: Amino Acids & Sleep PFC (mPFC) concentrations of Hist, asparagine (Asn), Asp, Microdialysates GABA, Glu, glutamine (Gln), Gly, proline (Pro) and Tau, Dialysate samples were collected for 1h periods (i.e. 180 analysing left-over microdialysis sample volume from μl) in plastic vials (300 μl; 7431100, Aurora Borealis) in another experiment [12]. We selected these amino acids a refrigerated fraction collector (6°C; CMA 470, Aurora as they can be measured in a single UPLC run [13, 14]. Borealis). Samples were transferred to ice during the Because this experiment was a spin-off, we did not have experiment and split into 8 fractions. The fractions des- clear a priori hypotheses on concentration changes, nor tined for Hist and amino acid measurements were trans- did we specifically design our experiment for measure- ported on dry ice from Amsterdam to Beerse, where they ments of amino acids. The experiment should be con- were again stored at −80°C until analysis. After the experi- sidered hypothesis-generating. Also, we did not analyse ment, all fractions were stored at −80°C. Corticosterone the literature on amino acids in detail upfront. To put [12], adenosine [7] and monoamines [6] were determined our data into perspective, we did perform a systematic in other fractions. review (SR) of sleep and sleep deprivation studies meas- Hist and amino acids were determined by Janssen uring these molecules in animal brain microdialysates Pharmaceutica, Research & Development (Beerse, afterwards. Belgium), department of Neuroscience Systems Biology. The standard protocol comprises UPLC with fluorescent Materials and Methods detection (UPLC-FD) after derivatization with 6-amino- mPFC Microdialysis Experiment quinolyl-N-hydroxy-succinimidyl-carbamate (AQC), as Our experimental protocol has been described previously, described before by Cohen et al. [13] and Liu et al. [14]. with measurements of dialysate corticosterone [12], aden- osine [7] and monoamine concentrations [6] before, dur- Primary Data-Analysis ing and after sleep deprivation. We now describe Hist and Analyses of our experimental data were performed in the amino acids Asn, Asp, GABA, Glu, Gln, Gly, Pro and Microsoft Excel and SPSS 24.0.0.0. In line with our anal- Tau. We restricted our analysis to these molecules, as they yses for monoamines [6] and adenosine [7], we selected can be measured in a single UPLC run. A comparable pub- analyses that limit the effects of outliers on the results. lication on monoamines measured in the same dialysates We thus report median values and the interquartile range can be found in Menon et al. [6]. (IQR) for each phase of the experiment, instead of the gen- In short, male Wistar rats (N = 11, 250–300g) were erally reported mean ± standard error. prepared for microdialysis with custom-made (e.g. The median of the 12h blocks for baseline–light, [15]) concentric microdialysis probes (the probe was baseline–dark, sleep deprivation and recovery were deter- implanted directly, without the use of a guide cannula; mined for each animal. Differences between these phases exposed membrane length: 4 mm), placed into the were analysed with a non-parametric Friedman repeated- mPFC at an angle of 12° (AP + 3.0 mm; L ± 1.8 mm; measures test for each analysed molecule separately. V−5.5 mm; relative to Bregma) [16]. The experiment When the Friedman test indicated an overall significant started after approximately 1 week of post-surgical difference, post-hoc Wilcoxon signed rank tests were recovery. Rats were placed into separate compartments used to compare the sleep deprivation and recovery peri- of a sleep deprivation device after connection to the ods with their corresponding baseline, and to compare microdialysis set-up. Perfusion of artificial cerebro- baseline light phase with baseline dark phase. No other post-hoc tests were performed. spinal fluid (145 mmol/l NaCl, 1.2 mmol/l CaCl2, 2.7 mmol/l KCl, 1.0 mmol/l MgCl2) was set at a flow rate of 3 μl/min. Sampling continued for 64h, comprising Systematic Review 12h of wash-out and simultaneous habituation to the We previously published a systematic mapping review on experimental environment (19:00–07:00), 24h of base- Hist and the amino acids Asn, Asp, GABA, Glu, Gln, Gly, line (07:00–07:00), 12h of sleep deprivation during the Pro and Tau as assessed by intracerebral microdialysis [17]. light phase (modelling one sleepless night in humans; In this SR, we followed the same methodology up to the (07:00–19:00) and 16h of recovery (19:00–11:00). Sleep selection of papers. deprivation was achieved using variable forced locomo- tion in an upright rotating drum, divided into 2 semi- Search circular compartments by a stationary
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