Altered expression and functions of serotonin 5-HT1A and 5-HT1B receptors in knock-out mice lacking the 5-HT transporter.
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.
Fabre
V
V
INSERM U288, Neuropsychopharmacologie Moléculaire, Cellulaire et Fonctionnelle, Faculté de Médecine Pitié-Salpêtrière, Paris, France. vfabre@scripps.edu
Beaufour
C
C
Evrard
A
A
Rioux
A
A
Hanoun
N
N
Lesch
K P
KP
Murphy
D L
DL
Lanfumey
L
L
Hamon
M
M
Martres
M P
MP
D000818:Animals; D017660:Autoreceptors / Q000235:genetics / Q000378:metabolism; D001667:Binding, Competitive / Q000502:physiology; D001923:Brain Chemistry / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D015283:Citalopram / Q000494:pharmacology; D004151:Dipeptides / Q000378:metabolism / Q000494:pharmacology; D015536:Down-Regulation / Q000235:genetics; D019204:GTP-Binding Proteins / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism / Q000494:pharmacology; D006897:Hydroxyindoleacetic Acid / Q000032:analysis / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins; D010069:Oxadiazoles / Q000494:pharmacology; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000235:genetics* / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000032:analysis / Q000378:metabolism; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists / Q000378:metabolism / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013141:Spiro Compounds / Q000378:metabolism / Q000494:pharmacology; D013378:Substantia Nigra / Q000378:metabolism; D013462:Sulfur Radioisotopes; D009435:Synaptic Transmission / Q000502:physiology; D014316:Tritium
D017660:Autoreceptors; D002352:Carrier Proteins; D015283:Citalopram; D004151:Dipeptides; D019204:GTP-Binding Proteins; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D006897:Hydroxyindoleacetic Acid; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010069:Oxadiazoles; D010879:Piperazines; D011725:Pyridines; D011743:Pyrimidines; D012333:RNA, Messenger; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; D013141:Spiro Compounds; D013462:Sulfur Radioisotopes; D014316:Tritium; C493231:Slc6a4 protein, mouse; C090701:GR 127935; C075319:alnespirone; C093209:glycyltyrosinamide; C043077:ipsapirone; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide