Abstract
By taking up serotonin (5-hydroxytryptamine, 5-HT) released in the extracellular space, the 5-HT transporter (5-HTT) regulates central 5-HT neurotransmission. Possible adaptive changes in 5-HT neurotransmission in knock-out mice that do not express the 5-HT transporter were investigated with special focus on 5-HT1A and 5-HT1B receptors. Specific labelling with radioligands and antibodies, and competitive RT-PCR, showed that 5-HT1A receptor protein and mRNA levels were significantly decreased in the dorsal raphe nucleus (DRN), increased in the hippocampus and unchanged in other forebrain areas of 5-HTT-/- vs. 5-HTT+/+ mice. Such regional differences also concerned 5-HT1B receptors because a decrease in their density was found in the substantia nigra (-30%) but not the globus pallidus of mutant mice. Intermediate changes were noted in 5-HTT+/- mice compared with 5-HTT+/+ and 5-HTT-/- animals. Quantification of [35S]GTP-gamma-S binding evoked by potent 5-HT1 receptor agonists confirmed such changes as a decrease in this parameter was noted in the DRN (-66%) and the substantia nigra (-30%) but not other brain areas in 5-HTT-/- vs. 5-HTT+/+ mice. As expected from actions mediated by functional 5-HT1A and 5-HT1B autoreceptors, a decrease in brain 5-HT turnover rate after i.p. administration of ipsapirone (a 5-HT1A agonist), and an increased 5-HT outflow in the substantia nigra upon local application of GR 127935 (a 5-HT1B/1D antagonist) were observed in 5-HTT+/+ mice. Such effects were not detected in 5-HTT-/- mice, further confirming the occurrence of marked alterations of 5-HT1A and 5-HT1B autoreceptors in these animals.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Autoreceptors / genetics
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Autoreceptors / metabolism
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Binding, Competitive / physiology
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Brain Chemistry / genetics*
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Carrier Proteins / genetics*
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Carrier Proteins / metabolism
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Citalopram / pharmacology
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Dipeptides / metabolism
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Dipeptides / pharmacology
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Down-Regulation / genetics
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GTP-Binding Proteins / metabolism
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Gene Expression / drug effects
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Gene Expression / physiology
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Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
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Guanosine 5'-O-(3-Thiotriphosphate) / pharmacology
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Hydroxyindoleacetic Acid / analysis
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Hydroxyindoleacetic Acid / metabolism
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Male
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Membrane Glycoproteins / genetics*
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Membrane Glycoproteins / metabolism
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Membrane Transport Proteins*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Nerve Tissue Proteins*
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Oxadiazoles / pharmacology
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Piperazines / metabolism
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Piperazines / pharmacology
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Pyridines / metabolism
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Pyridines / pharmacology
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Pyrimidines / pharmacology
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RNA, Messenger / analysis
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Receptor, Serotonin, 5-HT1B
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Receptors, Serotonin / genetics*
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Receptors, Serotonin / metabolism
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Receptors, Serotonin, 5-HT1
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Selective Serotonin Reuptake Inhibitors / pharmacology
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Serotonin / analysis
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Serotonin / metabolism
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Serotonin Antagonists / metabolism
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Serotonin Antagonists / pharmacology
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Serotonin Plasma Membrane Transport Proteins
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Serotonin Receptor Agonists / metabolism
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Serotonin Receptor Agonists / pharmacology
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Spiro Compounds / metabolism
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Spiro Compounds / pharmacology
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Substantia Nigra / metabolism
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Sulfur Radioisotopes
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Synaptic Transmission / physiology
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Tritium
Substances
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Autoreceptors
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Carrier Proteins
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Dipeptides
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Membrane Glycoproteins
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Membrane Transport Proteins
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Nerve Tissue Proteins
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Oxadiazoles
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Piperazines
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Pyridines
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Pyrimidines
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RNA, Messenger
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Receptor, Serotonin, 5-HT1B
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Receptors, Serotonin
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Receptors, Serotonin, 5-HT1
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Serotonin Antagonists
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Serotonin Plasma Membrane Transport Proteins
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Serotonin Receptor Agonists
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Serotonin Uptake Inhibitors
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Slc6a4 protein, mouse
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Spiro Compounds
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Sulfur Radioisotopes
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Citalopram
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Tritium
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GR 127935
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Serotonin
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alnespirone
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glycyltyrosinamide
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Guanosine 5'-O-(3-Thiotriphosphate)
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Hydroxyindoleacetic Acid
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ipsapirone
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N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
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GTP-Binding Proteins