The neurotransmitter serotonin (5-HT), widely distributed in the central nervous system (CNS), is involved in a large variety of physiological functions. In several brain regions 5-HT is diffusely released by volume transmission and behaves as a neuromodulator rather than as a “classical” neurotransmitter. In some cases 5-HT is co-localized in the same nerve terminal with other neurotransmitters and reciprocal interactions take place. This review will focus on the modulatory action of 5-HT on the effects of glutamate and γ-amino-butyric acid (GABA), which are the principal neurotransmitters mediating respectively excitatory and inhibitory signals in the CNS. Examples of interaction at pre-and/or post-synaptic levels will be illustrated, as well as the receptors involved and their mechanisms of action. Finally, the physiological meaning of neuromodulatory effects of 5-HT will be briefly discussed with respect to pathologies deriving from malfunctioning of serotonin system.
Serotonin; neuromodulation; GABA; glutamate; cognition; nociception; motor control
Steroid hormone, progesterone, modulates neuroendocrine functions in the central nervous system resulting in alterations in physiology and behavior. These neuronal effects are mediated primarily by intracellular progestin receptors (PRs) in the steroid-sensitive neurons, resulting in transcription-dependent genomic actions (classical mechanism). In addition to progesterone, intracellular PRs can also be activated in a “ligand-independent” manner by neurotransmitters, peptide growth factors, cyclic nucleotides, and neurosteroids. Recent studies indicate that rapid, non-classical progesterone actions involving cytoplasmic kinase signaling and/or extranuclear PRs can result in both transcription-independent and transcription-dependent actions. Cross-talk between extranuclear and classical intracellular signaling pathways promotes progesterone-dependent behavior in mammals. This review focuses on the mechanisms by which progesterone-initiated signaling mechanisms converge with PRs in the brain to modulate reproductive behavior in female rodents.
progesterone; progestin receptors; dopamine; non-classical; signaling; cross-talk
The neurotrophins (NTs) have recently been shown to elicit pronounced effects on quantal neurotransmitter release at both central and peripheral nervous system synapses. Due to their activity-dependent release, as well as the subcellular localization of both protein and receptor, NTs are ideally suited to modify the strength of neuronal connections by “fine-tuning” synaptic activity through direct actions at presynaptic terminals. Here, using BDNF as a prototypical example, the authors provide an update of recent evidence demonstrating that NTs enhance quantal neurotransmitter release at synapses through presynaptic mechanisms. The authors further propose that a potential target for NT actions at presynaptic terminals is the mechanism by which terminals retrieve synaptic vesicles after exocytosis. Depending on the temporal demands placed on synapses during high-frequency synaptic transmission, synapses may use two alternative modes of synaptic vesicle retrieval, the conventional slow endosomal recycling or a faster rapid retrieval at the active zone, referred to as “kiss-and-run.” By modulating Ca2+ microdomains associated with voltage-gated Ca2+ channels at active zones, NTs may elicit a switch from the slow to the fast mode of endocytosis of vesicles at presynaptic terminals during high-frequency synaptic transmission, allowing more reliable information transfer and neuronal signaling in the central nervous system.
BDNF; Docked vesicles; Fusion pore; Hippocampus; mEPSC; Poisson stimulation; Quantal release; SNARE proteins; Synaptic vesicles; TrkB; Voltage-gated Ca2+ channels
The benzodiazepines are among the most widely used drugs in the world. When first introduced, little was known about their mechanism of action. However, in the last 20 years, our understanding of the chemistry and function of the central nervous system (CNS) has increased substantially. This knowledge has shed some light on the mechanism of action of the benzodiazepines and other centrally acting drugs. It is well established that the benzodiazepines act by combining with specific receptors in the central nervous system. These receptors are anatomically in close association with gamma amino butyric acid (GABA) receptors and appear to reside on the neuronal membrane in the same supramolecular protein complex. GABA is the major inhibitory neurotransmitter of the CNS. The benzodiazepines act by increasing the affinity of the GABA receptor for its ligand, thereby augmenting the inhibitory effect of a given concentration of GABA. Two hypotheses of benzodiazepine ligand-receptor interactions in this supramolecular protein complex have been proposed: (1) multiple receptor subtypes analogous to the opioid receptors; (2) single receptor with multiple conformations. The multiple receptor hypothesis suggests that each pharmacologic effect of the benzodiazepines (i.e., anxiolysis) is mediated by interaction with a specific receptor subtype. On the other hand, the alternative hypothesis suggests that only one receptor exists which has a dynamic conformation. Experimental evidence in support of each hypothesis is presented and critically evaluated.
The hop (Humulus lupulus L.), a component of beer, is a sedative plant whose pharmacological activity is principally due to its bitter resins, in particular to the α-acid degradation product 2-methyl-3-buten-2-ol. The mechanism of action of hop resin consists of raising the levels of the neurotransmitter γ-aminobutyric acid (GABA), an inhibitory neurotransmitter acting in the central nervous system (CNS).
To analyze the sedative effect of hops as a component of non-alcoholic beer on the sleep/wake rhythm in a work-stressed population.
The experiment was conducted with healthy female nurses (n = 17) working rotating and/or night shifts. Overnight sleep and chronobiological parameters were assessed by actigraphy (Actiwatch®) after moderate ingestion of non-alcoholic beer containing hops (333 ml with 0,0% alcohol) with supper for 14 days (treatment). Data were obtained in comparison with her own control group without consumption of beer during supper.
Actigraphy results demonstrated improvement of night sleep quality as regards the most important parameters: Sleep Latency diminished (p≤0.05) in the Treatment group (12.01±1.19 min) when compared to the Control group (20.50±4.21 min), as also did Total Activity (p≤0.05; Treatment group = 5284.78±836.99 activity pulses vs Control = 7258.78±898.89 activity pulses). In addition, anxiety as indexed by the State-Trait Anxiety Inventory (STAI) decreased in the Treatment group (State Anxiety 18.09±3.8 vs Control 20.69±2.14).
The moderate consumption of non-alcoholic beer will favour night-time rest, due in particular to its hop components, in addition to its other confirmed benefits for the organism.
Endocannabinoids (eCBs) inhibit neurotransmitter release throughout the central nervous system. Using the Ceratomandibularis muscle from the lizard Anolis carolinensis we asked whether eCBs play a similar role at the vertebrate neuromuscular junction. We report here that the CB1 cannabinoid receptor is concentrated on motor terminals and that eCBs mediate the inhibition of neurotransmitter release induced by the activation of M3 muscarinic acetylcholine (ACh) receptors. N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide, a CB1 antagonist, prevents muscarine from inhibiting release and arachidonylcyclopropylamide (ACPA), a CB1 receptor agonist, mimics M3 activation and occludes the effect of muscarine. As for its mechanism of action, ACPA reduces the action-potential-evoked calcium transient in the nerve terminal and this decrease is more than sufficient to account for the observed inhibition of neurotransmitter release. Similar to muscarine, the inhibition of synaptic transmission by ACPA requires nitric oxide, acting via the synthesis of cGMP and the activation of cGMP-dependent protein kinase. 2-Arachidonoylglycerol (2-AG) is responsible for the majority of the effects of eCB as inhibitors of phospholipase C and diacylglycerol lipase, two enzymes responsible for synthesis of 2-AG, significantly limit muscarine-induced inhibition of neurotransmitter release. Lastly, the injection of (5Z,8Z,11Z,14Z)-N-(4-hydroxy-2-methylphenyl)-5,8,11,14-eicosatetraenamide (an inhibitor of eCB transport) into the muscle prevents muscarine, but not ACPA, from inhibiting ACh release. These results collectively lead to a model of the vertebrate neuromuscular junction whereby 2-AG mediates the muscarine-induced inhibition of ACh release. To demonstrate the physiological relevance of this model we show that the CB1 antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide prevents synaptic inhibition induced by 20 min of 1-Hz stimulation.
Anolis carolinensis; endocannabinoids; muscarinic; neuromuscular junction; synaptic depression
Regulated neurotransmitter actions in the mammalian central nervous system determine brain function and control peripheral organs and behavior. Although drug-seeking behaviors, including alcohol consumption, depend on central neurotransmission, modification of neurotransmitter actions in specific brain nuclei remains challenging. Herein, we report a novel approach for neurotransmission modification in vivo by transplantation of stem cells engineered to take up the neurotransmitter dopamine (DA) efficiently through the action of the human dopamine transporter (hDAT). As a functional test in mice, we used voluntary alcohol consumption, which is known to release DA in nucleus accumbens (NAC), an event hypothesized to help maintain drug-seeking behavior. We reasoned that reducing extracellular DA levels, by engrafting into NAC DA-sequestering stem cells expressing hDAT, would alter alcohol intake.
We have generated a neural stem cell line stably expressing the hDAT. Uptake kinetics of DA were determined to select a clone for transplantation. These genetically modified stem cells (or cells transfected with a construct lacking the hDAT sequence) were transplanted bilaterally into the NAC of wild-type mice trained to consume 10% alcohol in a two-bottle free-choice test for alcohol consumption. Alcohol intake was then ascertained for 1 week after transplantation, and brain sections through the NAC were examined for surviving grafted cells.
Modified stem cells expressed hDAT and uptaken DA selectively via hDAT. Mice accustomed to drinking 10% ethanol by free choice reduced their alcohol consumption after being transplanted with hDAT-expressing stem cells. By contrast, control stem cells lacked that effect. Histologic examination revealed surviving stem cells in the NAC of all engrafted brains.
Our findings represent proof of principle suggesting that genetically engineered stem cells can be useful for exploring the role of neurotransmitters (or other signaling molecules) in alcohol consumption and potentially in other aspects of brain function.
Metabolite distribution imaging via imaging mass spectrometry (IMS) is an increasingly utilized tool in the field of neurochemistry. As most previous IMS studies analyzed the relative abundances of larger metabolite species, it is important to expand its application to smaller molecules, such as neurotransmitters. This study aimed to develop an IMS application to visualize neurotransmitter distribution in central nervous system tissue sections. Here, we raise two technical problems that must be resolved to achieve neurotransmitter imaging: (1) the lower concentrations of bioactive molecules, compared with those of membrane lipids, require higher sensitivity and/or signal-to-noise (S/N) ratios in signal detection, and (2) the molecular turnover of the neurotransmitters is rapid; thus, tissue preparation procedures should be performed carefully to minimize postmortem changes. We first evaluated intrinsic sensitivity and matrix interference using Matrix Assisted Laser Desorption/Ionization (MALDI) mass spectrometry (MS) to detect six neurotransmitters and chose acetylcholine (ACh) as a model for study. Next, we examined both single MS imaging and MS/MS imaging for ACh and found that via an ion transition from m/z 146 to m/z 87 in MS/MS imaging, ACh could be visualized with a high S/N ratio. Furthermore, we found that in situ freezing method of brain samples improved IMS data quality in terms of the number of effective pixels and the image contrast (i.e., the sensitivity and dynamic range). Therefore, by addressing the aforementioned problems, we demonstrated the tissue distribution of ACh, the most suitable molecular specimen for positive ion detection by IMS, to reveal its localization in central nervous system tissues.
Imaging mass spectrometry; Neurotransmitter; Acetylcholine; MS; MS/MS; Imaging; IMS
In the mature mammalian auditory system, inner hair cells are responsible for converting sound-evoked vibrations into graded electrical responses, resulting in release of neurotransmitter and neuronal transmission via the VIIIth cranial nerve to auditory centres in the central nervous system. Before the cochlea can reliably respond to sound, inner hair cells are not merely immature quiescent pre-hearing cells, but instead are capable of generating ‘spontaneous’ calcium-based action potentials. The resulting calcium signal promotes transmitter release that drives action potential firing in developing spiral ganglion neurones. These early signalling events that occur before sound-evoked activity are thought to be important in guiding and refining the initial phases of development of the auditory circuits. This review will summarise our current knowledge of the mechanisms that underlie spontaneous action potentials in developing inner hair cells and how these events are triggered and regulated.
action potentials; calcium; inner hair cells; cochlea; development; auditory; spiral ganglion neuron
Mood disorders are common and debilitating, resulting in a significant public health burden. Current treatments are only partly effective and patients who have failed to respond to trials of existing antidepressant agents (eg, those who suffer from treatment-resistant depression [TRD]) require innovative therapeutics with novel mechanisms of action. Although neuroscience research has elucidated important aspects of the basic mechanisms of antidepressant action, most antidepressant drugs target monoaminergic mechanisms identified decades ago. Glutamate, the major excitatory neurotransmitter in the central nervous system, and glutamatergic dysfunction has been implicated in mood disorders. These data provide a rationale for the pursuit of glutamatergic agents as novel therapeutic agents. Here, we review preclinical and clinical investigations of glutamatergic agents in mood disorders with a focus on depression. We begin with discussion of evidence for the rapid antidepressant effects of ketamine, followed by studies of the antidepressant efficacy of the currently marketed drugs riluzole and lamotrigine. Promising novel agents currently in development, including N-methyl-D-aspartate (NMDA) receptor modulators, 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid (AMPA) receptor modulators, and drugs with activity at the metabotropic glutamate (mGlu) receptors are then reviewed. Taken together, both preclinical and clinical evidence exists to support the pursuit of small molecule modulators of the glutamate system as novel therapeutic agents in mood disorders. It is hoped that by targeting neural systems outside of the monoamine system, more effective and perhaps faster acting therapeutics can be developed for patients suffering from these disabling disorders.
glutamate; mood disorders; major depressive disorder; ketamine; NMDA; AMPA
The molecular mechanisms of general anaesthetics have remained largely obscure since their introduction into clinical practice just over 150 years ago. This review describes the actions of general anaesthetics on mammalian neurotransmitter-gated ion channels. As a result of research during the last several decades, ligand-gated ion channels have emerged as promising molecular targets for the central nervous system effects of general anaesthetics. The last 10 years have witnessed an explosion of studies of anaesthetic modulation of recombinant ligand-gated ion channels, including recent studies which utilize chimeric and mutated receptors to identify regions of ligand-gated ion channels important for the actions of general anaesthetics. Exciting future directions include structural biology and gene-targeting approaches to further the understanding of general anaesthetic molecular mechanisms.
General anaesthesia; ligand-gated ion channels; GABA; glutamine; acetylcholine; glycine; serotonin; electrophysiology
Curcumin, the principal curcuminoid found in spice turmeric, has recently been studied for its active role in the treatment of various central nervous system disorders. Curcumin demonstrates neuroprotective action in Alzheimer's disease, tardive dyskinesia, major depression, epilepsy, and other related neurodegenerative and neuropsychiatric disorders. The mechanism of its neuroprotective action is not completely understood. However, it has been hypothesized to act majorly through its anti-inflammatory and antioxidant properties. Also, it is a potent inhibitor of reactive astrocyte expression and thus prevents cell death. Curcumin also modulates various neurotransmitter levels in the brain. The present review attempts to discuss some of the potential protective role of curcumin in animal models of major depression, tardive dyskinesia and diabetic neuropathy. These studies call for well planned clinical studies on curcumin for its potential use in neurological disorders.
Curcumin; diabetic neuropathy; major depression; tardive dyskinesia
A growing body of evidence supports carbon monoxide (CO) as a gas neurotransmitter within the central nervous system. While CO has been shown to affect neurohypophyseal hormone release in response to osmotic stimuli, the precise sources, targets and mechanisms underlying CO actions within the magnocellular neurosecretory system remain largely unknown. In this study, we combined immunohistochemistry and patch-clamp electrophysiology to study the cellular distribution of the CO-synthase enzyme heme oxygenase type 1 (HO-1), as well as CO actions on oxytocin (OT) and vasopressin (VP) magnocellular neurosecretory cells (MNCs) in euhydrated (EU) and 48h water-deprived rats (48WD). Our results show expression of HO-1 immunoreactivity both in OT and VP neurones, as well as in a small proportion of astrocytes, both in the supraoptic (SON) and paraventricular (PVN) nuclei. HO-1 expression, and its colocalization with OT and VP neurones within SON and PVN were significantly enhanced in 48WD rats. Inhibition of HO activity (CrMP 20μM) resulted in a slight membrane hyperpolarization in SON neurones from EU rats, without significantly affecting their firing activity. In 48WD rats, on the other hand, CrMP resulted in a more robust membrane hyperpolarization, significantly decreasing neuronal firing discharge. Taken together, our results indicate that magnocellular SON and PVN neurones express HO-1, and that CO acts as an excitatory gas neurotransmitter in this system. Moreover, we found the expression and actions of CO to be enhanced in water-deprived rats, suggesting that the state-dependent up-regulation of the HO-1/CO signalling pathway contributes to enhance MNCs firing activity during an osmotic challenge.
supraoptic; paraventricular; hypothalamus; dehydration; neuroendocrine
During the last 50 years the global pandemic of obesity and associated life-threatening co-morbidities strongly promoted the development of anti-obesity pharmacotherapy. Sibutramine is an anti-obesity drug that in conjunction with lifestyle modifications reduces food intake and body weight. This may result from several effects: inhibition of presynaptic reuptake of monoaminergic neurotransmitters in the central nervous system, thereby suppressing appetite, induction of an increase in anorexigenic and a decrease in orexigenic neuropeptide secretion, induction of an increase in energy expenditure, and induction of peripheral sympathomimetic effects. The effects of sibutramine on anabolic and catabolic signals that regulate energy homeostasis in the hypothalamus are not completely understood. So, the aim of this review is to summarize the central mechanisms of action of sibutramine, responsible for its weight and food intake reducing potential. Despite being a useful drug in obesity treatment, awareness about the loss of long-term effectiveness and detrimental side effects of sibutramine has recently emerged. As a consequence, new drugs that produce safer and more persistent weight loss are currently undergoing clinical trials.
Appetite; obesity; sibutramine; hypothalamus; weight loss.
Cholinergic neurons are a major constituent of the mammalian central nervous system. Acetylcholine, the neurotransmitter used by cholinergic neurons, is synthesized from choline and acetyl CoA by the enzymatic action of choline acetyltransferase (ChAT). The transport of choline into the cholinergic neurons, which results in synthesis of ACh, is hemicholinium sensitive and is referred to as high affinity choline uptake (HACU). Thus, the formation of acetylcholine in cholinergic neurons largely depends on both the levels of choline being transported into the cells from the extracellular space, and the activity of ChAT. Several methods were described previously to measure HACU and ChAT simultaneously in synaptosomes, but the same for cultured cells is lacking. We describe a procedure to measure HACU and ChAT at the same time in cultured cells by simple techniques employing radionuclides. In this procedure we determined quantitatively hemicholinium sensitive choline uptake, and ChAT enzyme activity in a small number of differentiated human neuroblastoma (SK-N-SH) cells. We also determined the kinetics of choline uptake in the SK-N-SH cells. We believe that these simple methods can be used for neurochemical and drug discovery studies in several models of neurodegenerative disorders including Alzheimer’s disease.
Acetylcholine; choline uptake; ChAT; differentiation; enzyme assay; HACU; neuronal cells; neurodegenerative disorders; tissue culture
GABAA receptors are located on the majority of neurons in the central and peripheral nervous system, where they mediate important actions of the neurotransmitter gamma-aminobutyric acid. Early in development the trophic properties of GABA allow a healthy development of the nervous system. Most neurons have a high intracellular Cl-concentration early in life due to the late functional expression of the Cl-pump KCC2, therefore GABA has excitatory effects at this stage. Upon higher expression and activation of KCC2 GABA takes on its inhibitory effects while glutamate functions as the major excitatory neurotransmitter. Like all multisubunit membrane proteins the GABAA receptor is assembled in the ER and travels through the Golgi and remaining secretory pathway to the cell surface, where it mediates GABA actions either directly at the synapses or at extrasynaptic sites responding to ambient GABA to provide a basal tonic inhibitory state. In order to adapt to changing needs and information states, the GABAergic system is highly dynamic. That includes subtype specific trafficking to different locations in the cell, regulation of mobility by interaction with scaffold molecules, posttranslational modifications, that either directly affect channel function or the interaction with other proteins and finally the dynamic exchange between surface and intracellular receptor pools, that either prepare receptors for recycling to the surface or degradation. Here we give an overview of the current understanding of GABAA receptor functional and molecular dynamics that play a major part in maintaining the balance between excitation and inhibition and in changes in network activity.
GABAA receptor; receptor trafficking; receptor clustering; inhibition
In recent years it has becoming clear that glial cells of the central and peripheral nervous system play a crucial role from the earliest stages of development throughout adult life. Glial cells are important for neuronal plasticity, axonal conduction and synaptic transmission. In this respect, glial cells are able to produce, uptake and metabolize many factors that are essential for neuronal physiology, including classic neurotransmitters and neuroactive steroids. In particular, neuroactive steroids, which are mainly synthesized by glial cells, are able to modulate some neurotransmitter receptors affecting both glia and neurons. Among the signaling systems that are specialized for neuron-glial communication, we can include neurotransmitter GABA.
The main focus of this review is to illustrate the cross-talk between neurons and glial cells in terms of GABA neurotransmission and actions of neuroactive steroids. To this purpose, we will review the presence of the different GABA receptors in the glial cells of the central and peripheral nervous system. Then, we will discuss their modulation by some neuroactive steroids.
GABA-A receptor; GABA-B receptor; neurosteroids; microglia; macroglia
In the central nervous system, most synapses show a fast mode of neurotransmitter release known as synchronous release followed by a phase of asynchronous release, which extends over tens of milliseconds to seconds. Synapsin II (SYN2) is a member of the multigene synapsin family (SYN1/2/3) of synaptic vesicle phosphoproteins that modulate synaptic transmission and plasticity, and are mutated in epileptic patients. Here we report that inhibitory synapses of the dentate gyrus of Syn II knockout mice display an upregulation of synchronous neurotransmitter release and a concomitant loss of delayed asynchronous release. Syn II promotes γ-aminobutyric acid asynchronous release in a Ca2+-dependent manner by a functional interaction with presynaptic Ca2+ channels, revealing a new role in synaptic transmission for synapsins.
The arrival of action potentials at nerve terminals often leads to synchronous neurotransmitter release. Medrihan and colleagues use electrophysiology on mouse hippocampal neurons to show that the vesicle protein Synapsin II promotes GABAergic asynchronous release by interacting with calcium channels.
The molecular mechanisms of modern inhaled anesthetics are still poorly understood although they are widely used in clinical settings. Considerable evidence supports effects on membrane proteins including ligand- and voltage-gated ion channels of excitable cells. Na+ channels are crucial to action potential initiation and propagation, and represent potential targets for volatile anesthetic effects on central nervous system depression. Inhibition of presynaptic Na+ channels leads to reduced neurotransmitter release at the synapse and could therefore contribute to the mechanisms by which volatile anesthetics produce their characteristic end points: amnesia, unconsciousness, and immobility. Early studies on crayfish and squid giant axon showed inhibition of Na+ currents by volatile anesthetics at high concentrations. Subsequent studies using native neuronal preparations and heterologous expression systems with various mammalian Na+ channel isoforms implicated inhibition of presynaptic Na+ channels in anesthetic actions at clinical concentrations. Volatile anesthetics reduce peak Na+ current (INa) and shift the voltage of half-maximal steady-state inactivation (h∞) toward more negative potentials, thus stabilizing the fast-inactivated state. Furthermore recovery from fast-inactivation is slowed, together with enhanced use-dependent block during pulse train protocols. These effects can depress presynaptic excitability, depolarization and Ca2+ entry, and ultimately reduce transmitter release. This reduction in transmitter release is more potent for glutamatergic compared to GABAergic terminals. Involvement of Na+ channel inhibition in mediating the immobility caused by volatile anesthetics has been demonstrated in animal studies, in which intrathecal infusion of the Na+ channel blocker tetrodotoxin increases volatile anesthetic potency, whereas infusion of the Na+ channels agonist veratridine reduces anesthetic potency. These studies indicate that inhibition of presynaptic Na+ channels by volatile anesthetics is involved in mediating some of their effects.
sodium channels; volatile anesthetics; presynaptic; anesthetic mechanism
Apnea of prematurity (AOP) is a common problem affecting premature infants, likely secondary to a “physiologic” immaturity of respiratory control that may be exacerbated by neonatal disease. These include altered ventilatory responses to hypoxia, hypercapnia, and altered sleep states, while the roles of gastroesophageal reflux and anemia remain controversial. Standard clinical management of the obstructive subtype of AOP includes prone positioning and continuous positive or nasal intermittent positive pressure ventilation to prevent pharyngeal collapse and alveolar atelectasis, while methylxanthine therapy is a mainstay of treatment of central apnea by stimulating the central nervous system and respiratory muscle function. Other therapies, including kangaroo care, red blood cell transfusions, and CO2 inhalation, require further study. The physiology and pathophysiology behind AOP are discussed, including the laryngeal chemoreflex and sensitivity to inhibitory neurotransmitters, as are the mechanisms by which different therapies may work and the potential long-term neurodevelopmental consequences of AOP and its treatment.
Apnea of prematurity; Premature infant; Neurodevelopment; Methylxanthine therapy; Continuous positive airway pressure
Sleep laboratory investigations constitute a unique noninvasive tool to analyze brain functioning, Polysomnographic recordings, even in the very early phase of development in humans, are mandatory in a developmental plan of a new sleep-acting compound. Sleep is also an interesting tool for the development of other drugs acting on the central nervous system (CNS), Indeed, changes in sleep electroencephalographic (EEG) characteristics are a very sensitive indication of the objective central effects of psychoactive drugs, and these changes are specific to the way the drug acts on the brain neurotransmitter systems. Moreover, new compounds can be compared with reference drugs in terms of the sleep EEG profile they induce. For instance, cognitive enhancers involving cholinergic mechanism have been consistently demonstrated to increase rapid eye movement (REM) sleep pressure, and studying drug-induced slow wave sleep (SWS) alteration is a particularly useful tool for the development of CNS compounds acting at the 5-HT2A/C receptor, such as most atypical antipsychotics and some antidepressant drugs. The sleep EEG profile of antidepressants, and particularly their effects on REM sleep, are specific to their ability to enhance noradrenergic or serotonergic transmission, it is suggested that the effects of noradrenergic versus serotonergic reuptake inhibition could be disentangled using specific monoamine depletion tests and by studying drug effects on sleep microsiructure.
rapid eye movement sleep; EEG; slow wave sleep; acetylcholine; depression
γ-Hydroxybutyric acid (GHB) is a naturally occurring γ-aminobutyric acid (GABA) metabolite that has been proposed as a neurotransmitter/neuromodulator that acts via its own receptor (GHBR). Its exogenous administration, however, elicits central nervous system-dependent effects (e.g. memory impairment, increase in sleep stages 3 and 4, dependence, seizures and coma) that are mostly mediated by GABAB receptors. The past few years have seen important developments in our understanding of GHB neurobiology: a putative GHBR has been cloned; a transgenic model of GHB aciduria has been developed; GABAB receptor knockout mice and novel GHB analogs have helped to characterize the vast majority of exogenous GHB actions mediated by GABAB receptors; and some of the cellular mechanisms underlying the dependence/abuse properties of GHB, and its ability to elicit absence seizures and an increase in sleep stages 3 and 4, have been clarified. Nevertheless, the physiological significance of a brain GHB signaling pathway is still unknown, and there is an urgent need for a well-validated functional assay for GHBRs. Moreover, as GHB can also be metabolized to GABA, it remains to be seen whether the many GABAB receptor-mediated actions of GHB are caused by GHB itself acting directly on GABAB receptors or by a GHB-derived GABA pool (or both).
General anaesthetics act in an agent-specific manner on synaptic transmission in the central nervous system by enhancing inhibitory transmission and reducing excitatory transmission. The synaptic mechanisms of general anaesthetics involve both presynaptic effects on transmitter release and postsynaptic effects on receptor function. The halogenated volatile anaesthetics inhibit neuronal voltage-gated Na+ channels at clinical concentrations. Reductions in neurotransmitter release by volatile anaesthetics involve inhibition of presynaptic action potentials as a result of Na+ channel blockade. Although voltage-gated ion channels have been assumed to be insensitive to general anaesthetics, it is now evident that clinical concentrations of volatile anaesthetics inhibit Na+ channels in isolated rat nerve terminals and neurons, as well as heterologously expressed mammalian Na+ channel α subunits. Voltage-gated Na+ channels have emerged as promising targets for some of the effects of the inhaled anaesthetics. Knowledge of the synaptic mechanisms of general anaesthetics is essential for optimization of anaesthetic techniques for advanced surgical procedures and for the development of improved anaesthetics.
anaesthetics volatile; anaesthetics volatile, halogenated hydrocarbons; nerve, neurotransmitters; pharmacology, anaesthetic action; pharmacology, neurotransmission
General anesthetics produce a widespread neurodepression in the central nervous system by enhancing inhibitory neurotransmission and reducing excitatory neurotransmission. However, the action mechanisms of general anesthetics are not completely understood. Moreover, the general anesthetic state comprises multiple components (amnesia, unconsciousness, analgesia, and immobility), each of which is mediated by different receptors and neuronal pathways. Recently, neurotransmitter- and voltage-gated ion channels have emerged as the most likely molecular targets for general anesthetics. The γ-aminobutyric acid type A (GABAA) receptors are leading candidates as a primary target of general anesthetics. This review summarizes current knowledge on how anesthetics modify GABAA receptor function.
GABAA receptors; General anesthetics; Neurotransmitter-gated ion channels
Glycine, a nonessential amino-acid that acts as an inhibitory neurotransmitter in the central nervous system, is currently used as a dietary supplement to improve the quality of sleep, but its mechanism of action is poorly understood. We confirmed the effects of glycine on sleep/wakefulness behavior in mice when administered peripherally. Glycine administration increased non-rapid eye movement (NREM) sleep time and decreased the amount and mean episode duration of wakefulness when administered in the dark period. Since peripheral administration of glycine induced fragmentation of sleep/wakefulness states, which is a characteristic of orexin deficiency, we examined the effects of glycine on orexin neurons. The number of Fos-positive orexin neurons markedly decreased after intraperitoneal administration of glycine to mice. To examine whether glycine acts directly on orexin neurons, we examined the effects of glycine on orexin neurons by patch-clamp electrophysiology. Glycine directly induced hyperpolarization and cessation of firing of orexin neurons. These responses were inhibited by a specific glycine receptor antagonist, strychnine. Triple-labeling immunofluorescent analysis showed close apposition of glycine transporter 2 (GlyT2)-immunoreactive glycinergic fibers onto orexin-immunoreactive neurons. Immunoelectron microscopic analysis revealed that GlyT2-immunoreactive terminals made symmetrical synaptic contacts with somata and dendrites of orexin neurons. Double-labeling immunoelectron microscopy demonstrated that glycine receptor alpha subunits were localized in the postsynaptic membrane of symmetrical inhibitory synapses on orexin neurons. Considering the importance of glycinergic regulation during REM sleep, our observations suggest that glycine injection might affect the activity of orexin neurons, and that glycinergic inhibition of orexin neurons might play a role in physiological sleep regulation.