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      Monitoring serotonin signaling on a subsecond time scale


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          Serotonin modulates a variety of processes throughout the brain, but it is perhaps best known for its involvement in the etiology and treatment of depressive disorders. Microdialysis studies have provided a clear picture of how ambient serotonin levels fluctuate with regard to behavioral states and pharmacological manipulation, and anatomical and electrophysiological studies describe the location and activity of serotonin and its targets. However, few techniques combine the temporal resolution, spatial precision, and chemical selectivity to directly evaluate serotonin release and uptake. Fast-scan cyclic voltammetry (FSCV) is an electrochemical method that can detect minute changes in neurotransmitter concentration on the same temporal and spatial dimensions as extrasynaptic neurotransmission. Subsecond measurements both in vivo and in brain slice preparations enable us to tease apart the processes of release and uptake. These studies have particularly highlighted the significance of regulatory mechanisms to proper functioning of the serotonin system. This article will review the findings of FSCV investigations of serotonergic neurotransmission and discuss this technique's potential in future studies of the serotonin system.

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          Most cited references 104

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          Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors.

           Á Pazos,  J. Palacios (1985)
          The distribution of serotonin-1 (5-HT1) receptors in the rat brain was studied by light microscopic quantitative autoradiography. Receptors were labeled with [3H]serotonin (5-[3H]HT), 8-hydroxy-2-[N-dipropylamino-3H]tetralin (8-OH- [3H]DPAT), [3H]LSD and [3H]mesulergine, and the densities quantified by microdensitometry with the aid of a computer-assisted image-analysis system. Competition experiments for 5-[3H]HT binding by several serotonin-1 agonists led to the identification of brain areas enriched in each one of the three subtypes of 5-HT1 recognition sites already described (5-HT1A, 5-HT1B, 5-HT1C). The existence of these 'selective' areas allowed a detailed pharmacological characterization of these sites to be made in a more precise manner than has been attained in membrane-binding studies. While 5-[3H]HT labeled with nanomolar affinity all the 5-HT1 subtypes, the other 3H-labeled ligands labeled selectively 5-HT1A (8-OH-[3H]DPAT), 5-HT1C ([3H]mesulergine) and both of them ([3H]LSD). Very high concentrations of 5-HT1 receptors were localized in the choroid plexus, lateroseptal nucleus, globus pallidus and ventral pallidum, dentate gyrus, dorsal subiculum, olivary pretectal nucleus, substantia nigra, reticular and external layer of the entorhinal cortex. The different fields of the hippocampus (CA1-CA4), some nuclei of the amygdaloid complex, the hypothalamic nuclei and the dorsal raphé, among others, also presented high concentrations of sites. Areas containing intermediate densities of 5-HT1 receptors included the claustrum, olfactory tubercle, accumbens, central grey and lateral cerebellar nucleus. The nucleus caudate-putamen and the cortex, at the different levels studied, presented receptor densities ranging from intermediate to low. Finally, in other brain areas--pons, medulla, spinal cord--only low or very low concentrations of 5-HT1 receptors were found. From the areas strongly enriched in 5-HT1 sites, dentate gyrus and septal nucleus contained 5-HT1A sites, while globus pallidus, dorsal subiculum, substantia nigra and olivary pretectal nucleus were enriched in 5-HT1B. The sites in the choroid plexus, which presented the highest density of receptors in the rat brain, were of the 5-HT1C subtype. The distribution of 5-HT1 receptors reported here is discussed in correlation with the distribution of serotoninergic neurons and fibers, the related anatomical pathways and the effects which appear to be mediated by these sites.
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            Cloning and expression of a functional serotonin transporter from rat brain.

            Selective antagonism of serotonin (5-hydroxytryptamine, 5HT) and noradrenaline transport by antidepressants is a key element in the 'amine' hypothesis of affective disorders. Uptake and/or transport sites of 5HT have been reported to be reduced in platelets of patients suffering from depression and in post-mortem brain samples of depressed patients and suicide victims. To date there has been little molecular information available on the structure and regulation of 5HT transporters. Using the polymerase chain reaction with degenerate oligonucleotides derived from two highly conserved regions of the transporters for noradrenaline and gamma-aminobutyric acid (GABA), we have identified a large family of related gene products expressed in rodent brain. One of these products hybridizes to a single 3.7-kilobase RNA restricted to rat midbrain and brainstem, where it is highly enriched within the serotonergic raphe complex. Transfection with a single 2.3-kilobase brainstem complementary DNA clone is sufficient to confer expression of a Na(+)-dependent 5HT transporter upon nonneural cells, with transport selectively and potently antagonized by 5HT uptake-specific antidepressants, including paroxetine, citalopram and fluoxetine.
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              The discovery of central monoamine neurons gave volume transmission to the wired brain.

              The dawn of chemical neuroanatomy in the CNS came with the discovery and mapping of the central dopamine, noradrenaline and 5-hydroxytryptamine neurons by means of transmitter histochemistry using the Falck-Hillarp formaldehyde fluorescence technique in the early 1960s. Our mapping of the central monoamine neurons was continued and further established with tyrosine hydroxylase, dopa decarboxylase and dopamine-beta-hydroxylase immunohistochemistry in collaboration with Menek Goldstein and Tomas Hökfelt. During recent years an evolutionary constraint in the nuclear parcellation of the DA, NA and 5-HT neurons was demonstrated in the order Rodentia and other mammals. The abundant existence of global monoamine varicose nerve terminal networks synthesizing, storing and releasing monoamines in various parts of the CNS, including the release of DA by tubero-infundibular DA neurons as a prolactin inhibitory factor from the external layer of the median eminence into the portal vessels and the appearance of extraneuronal DA fluorescence after, e.g., treatment with amphetamine in nialamide pretreated rats (Falck-Hillarp technique) were also remarkable observations. These observations and others like the discovery of transmitter-receptor mismatches opened up the possibility that monoamines were modulating the wired brain, built up mainly by glutamate and GABA neurons, through diffusion and flow in the extracellular fluid of the extracellular space and in the CSF. This transmission also involved long-distance channels along myelinated fibers and blood vessels and was called volume transmission (VT). The extracellular space (ECS), filled with a 3D matrix, plays a fundamental role in this communication. Energy gradients for signal migration in the ECS are produced via concentration, temperature and pressure gradients, the latter two allowing a flow of the ECF and CSF carrying the VT signals. The differential properties of the wiring transmission (WT) and VT circuits and communication channels will be discussed as well as the role of neurosteroids and oxytocin receptors in volume transmission leading to a new understanding of the integrative actions of neuronal-glial networks. The role of tunneling nanotubes with mitochondrial transfer in CNS inter alia as part of neuron-glia interactions will also be introduced representing a novel type of wiring transmission. The impact of the technicolour approach to the connectome for the future characterization of the wired networks of the brain is emphasized. Copyright 2009 Elsevier Ltd. All rights reserved.

                Author and article information

                Front Integr Neurosci
                Front Integr Neurosci
                Front. Integr. Neurosci.
                Frontiers in Integrative Neuroscience
                Frontiers Media S.A.
                05 June 2013
                : 7
                [1] 1Curriculum in Neurobiology, University of North Carolina Chapel Hill, NC, USA
                [2] 2Department of Chemistry, University of North Carolina Chapel Hill, NC, USA
                Author notes

                Edited by: Kae Nakamura, Kansai Medical University, Japan

                Reviewed by: Katie A. Jennings, Oxford University, UK; Paul A. Garris, Illinois State University, USA

                *Correspondence: R. Mark Wightman, Department of Chemistry, University of North Carolina, Campus Box 3290, Chapel Hill, NC 27599, USA e-mail: rmw@ 123456unc.edu
                Copyright © 2013 Dankoski and Wightman.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 104, Pages: 13, Words: 11132
                Review Article


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