Neuropsychopharmacology advance online publication (original) (raw)
Related papers
2006
Abnormalities in the regulation of neurotransmitter release and/or abnormal levels of extracellular neurotransmitter concentrations have remained core components of hypotheses on the neuronal foundations of behavioral and cognitive disorders and the symptoms of neuropsychiatric and neurodegenerative disorders. Furthermore, therapeutic drugs for the treatment of these disorders have been developed and categorized largely on the basis of their effects on neurotransmitter release and resulting receptor stimulation. This perspective stresses the theoretical and practical implications of hypotheses that address the dynamic nature of neurotransmitter dysregulation, including the multiple feedback mechanisms regulating synaptic processes, phasic and tonic components of neurotransmission, compartmentalized release, differentiation between dysregulation of basal vs activated release, and abnormal release from neuronal systems recruited by behavioral and cognitive activity. Several examples illustrate that the nature of the neurotransmitter dysregulation in animal models, including the direction of drug effects on neurotransmitter release, depends fundamentally on the state of activity of the neurotransmitter system of interest and on the behavioral and cognitive functions recruiting these systems. Evidence from evolving techniques for the measurement of neurotransmitter release at high spatial and temporal resolution is likely to advance hypotheses describing the pivotal role of neurotransmitter dysfunction in the development of essential symptoms of major neuropsychiatric disorders, and also to refine neuropharmacological mechanisms to serve as targets for new treatment approaches. The significance and usefulness of hypotheses concerning the abnormal regulation of the release of extracellular concentrations of primary messengers depend on the effective integration of emerging concepts describing the dynamic, compartmentalized, and activitydependent characteristics of dysregulated neurotransmitter systems.
In vitro reconstitution of neurotransmitter release
Neurochemical research, 1998
The vesicular hypothesis has stimulated fruitful investigations on many secreting systems. In the case of rapid synaptic transmission, however, the hypothesis has been found difficult to reconcile with a number of well established observations. Brief impulses of transmitter molecules (quanta) are emitted from nerve terminals at the arrival of an action potential by a mechanism which is under the control of multiple regulations. It is therefore not surprising that quantal release could be disrupted by experimental manipulation of a variety of cellular processes, such as a) transmitter uptake, synthesis, or transport, b) energy supply, c) calcium entry, sequestration and extrusion, d) exo- or endocytosis, e) expression of vesicular and plasmalemmal proteins, f) modulatory systems and second messengers, g) cytoskeleton integrity, etc. Hence, the approaches by "ablation strategy" do not provide unequivocal information on the final step of the release process since there are so...
Neurotransmitters and Their Receptors – 2003
EJIFCC, 2004
Much has recently been discovered and achieved in the research of neurotransmitters, and much has already been incorporated and elaborated in textbooks and handbooks. Of course, any review of these plentiful new concepts would be more or less subjective unless a longer time is allowed to elapse in-between. Like all other scientific fields, the research of neurotransmitters is characterized by the exponential growth of novel concepts. In contrast, due to the time-consuming nature of drug trials, which is dictated by the ever rising professional demands and safety requirements to be met by new drugs, this inapparent segment of these studies advances at a much slower pace, thus practicing physicians may frequently perceive the amount of novelties in the field to be rather modest. However, the possibility for novel achievements to be utilized in laboratory diagnosis lies somewhere in-between the basic discoveries and the progress in pharmacotherapy.
Current Neuropharmacology, 2014
To understand better the cerebral functions, several methods have been developed to study the brain activity, they could be related with morphological, electrophysiological, molecular and neurochemical techniques. Monitoring neurotransmitter concentration is a key role to know better how the brain works during normal or pathological conditions, as well as for studying the changes in neurotransmitter concentration with the use of several drugs that could affect or reestablish the normal brain activity. Immediate response of the brain to environmental conditions is related with the release of the fast acting neurotransmission by glutamate (Glu), γ-aminobutyric acid (GABA) and acetylcholine (ACh) through the opening of ligand-operated ion channels. Neurotransmitter release is mainly determined by the classical microdialysis technique, this is generally coupled to high performance liquid chromatography (HPLC). Detection of neurotransmitters can be done by fluorescence, optical density, electrochemistry or other detection systems more sophisticated. Although the microdialysis method is the golden technique to monitor the brain neurotransmitters, it has a poor temporal resolution. Recently, with the use of biosensor the drawback of temporal resolution has been improved considerably, however other inconveniences have merged, such as stability, reproducibility and the lack of reliable biosensors mainly for GABA. The aim of this review is to show the important advances in the different ways to measure neurotransmitter concentrations; both with the use of classic techniques as well as with the novel methods and alternant approaches to improve the temporal resolution.
Neurotransmitter release: Development of a theory for total release based on kinetics
Journal of Theoretical Biology, 1989
According to the calcium-voltage hypothesis for the control of neurotransmitter release, a molecule (or molecular complex) must be activated by membrane depolarization, after which the activated molecule can bind calcium and initiate release. In this study, we have examined properties of the kinetics of phasic release resulting from a set of differential equations that characterize the calcium-voltage hypothesis. It was found that, in accord with experiments, an important feature is the approximate constancy of the shape of the graph for the kinetics of phasic release at various depolarizations and extracellular calcium concentrations. The shape constancy allowed us to obtain an explicit and relatively simple analytical formula for the total transmitter release (quantal content) by approximating the differential equations of the model. This formula shows a saturating sigmoidal dependence on both intracellular and extracellular calcium concentrations. The formula thus agrees with various experiments. Moreover, it agrees with, and provides meaning to, earlier phenomenological expressions for the dependence of release on calcium concentration. In particular, the formula provides an expression for the maximal release in terms of kinetic parameters from the calcium-voltage model, and thereby allows one to supplement earlier kinetic tests of the calcium-voltage hypothesis with further tests focused upon the dependence of total release on depolarization.
Patterns of neurotransmitter receptor distributions following cortical spreading depression
Neuroscience, 2009
Spreading depression (SD), a self-propagating depolarization of neurons and glia, is believed to play a role in different neurological disorders including migraine aura and acute brain ischaemia. Initiation and propagation of SD modulate excitability of neuronal network. A brief period of excitation heralds SD which is immediately followed first by prolonged nerve cell depression and later by an excitatory phase. The aim of the present study was to characterize local and remote transmitter receptor changes after propagation of cortical SD. Quantitative receptor autoradiography was used to asses 16 transmitter receptor types in combined striatumhippocampus-cortex slices of the rat 1 h after induction of cortical SD. In neocortical tissues, local increases of glutamate NMDA, AMPA, and kainate receptor binding sites were observed. In addition to up-regulation of ionotropic glutamate receptors, receptor binding sites of GABA A , muscarinic M1 and M2, adrenergic ␣ 1 and ␣ 2 , and serotonergic 5-HT 2 receptors were increased in the hippocampus. Cortical SD also upregulated NMDA, AMPA, kainate, GABA A , serotonergic 5-HT 2 , adrenergic ␣ 2 and dopaminergic D1 receptor binding sites in the striatum. These findings indicate selective changes in several receptors binding sites both in cortical and subcortical regions by SD which may explain delayed excitatory phase after SD. Mapping of receptor changes by cortical SD increases our understanding of the mechanism of SD action in associated neurological disorders.
International Journal of Molecular Sciences
Neurotransmitters are molecules that amplify, transmit, and convert signals in cells, having an essential role in information transmission throughout the nervous system. Hundreds of such chemicals have been discovered in the last century, continuing to be identified and studied concerning their action on brain health. These substances have been observed to influence numerous functions, including emotions, thoughts, memories, learning, and movements. Thus, disturbances in neurotransmitters’ homeostasis started being correlated with a plethora of neurological and neurodegenerative disorders. In this respect, the present paper aims to describe the most important neurotransmitters, broadly classified into canonical (e.g., amino acids, monoamines, acetylcholine, purines, soluble gases, neuropeptides) and noncanonical neurotransmitters (e.g., exosomes, steroids, D-aspartic acid), and explain their link with some of the most relevant neurological conditions. Moreover, a brief overview of t...
Second messenger pathways in the modulation of neurotransmitter release
1995
Activation of receptors on postganglionic sympathetic nerve endings can alter the amount of noradrenaline release during a train of nerve impulses. These changes may be produced by the enzyme-linked synthesis of second messenger molecules within the nerve terminal. Cyclic A M P analogues enhance noradrenaline release and two hormones adrenaline and A C T H appear to enhance noradrenaline release through activation of aa'enylate cyclase. Activation of the phospholipase Uprotein kinase C pathway also elevates stimulation-induced noradrenaline release and angiotensin enhancement of noradrenaline release appears to act through this pathway. On the other hand, receptors which inhibit noradrenaline release (aladrenoceptors, muscarinic M , receptors and neuropeptide Y receptors) do not act through either of these signal transduction pathways. Since these inhibit0 y systems are neurotransmitter activated and relay information on a nerve pulse to nerve pulse time scale back to the nerve ending a fast activation and deactivation rate of modulation is required. This may be better served by direct modulation of ion channels without a slow intervening enzyme step.