Altered regulation of the 5-HT system in the brain of MAO-A knock-out mice.
Genetic deficiency of monoamine oxidase-A (MAO-A) induces major alterations of mood and behaviour in human. Because serotonin (5-HT) is involved in mood regulation, and MAO-A is responsible for the catabolism of 5-HT, we investigated 5-HT mechanisms in knock-out mice (2-month-old) lacking MAO-A, using microdialysis, electrophysiological, autoradiographic and molecular biology approaches. Compared to paired wild-type mice, basal extracellular 5-HT levels were increased in ventral hippocampus (+202%), frontal cortex (+96%) and dorsal raphe nucleus (DRN, +147%) of MAO-A mutant mice. Conversely, spontaneous firing rate of 5-HT neurons in the DRN (recorded under chloral hydrate anaesthesia) was approximately 40% lower in mutants. Acute 5-HT reuptake blockade by citalopram (0.2 and 0.8 mg/kg i.v.) produced a much larger increase in extracellular 5-HT levels (by approximately 4 fold) and decrease in DRN neuronal firing (with a approximately 4.5 fold decrease in the drug's ED50) in MAO-A knock-out mice, which expressed lower levels of the 5-HT transporter throughout the brain (-13 to -34% compared to wild-type levels). The potency of the 5-HT1A agonist 8-OH-DPAT to produce hypothermia and to reduce the firing of DRN serotoninergic neurons was significantly less in the mutants, indicating a desensitization of 5-HT1A autoreceptors. This was associated with a decreased autoradiographic labelling of these receptors (-27%) in the DRN. Altogether, these data indicate that, in MAO-A knock-out mice, the enhancement of extracellular 5-HT levels induces a down-regulation of the 5-HT transporter, and a desensitization of 5-HT1A autoreceptors which allows the maintenance of tonic activity of 5-HT neurons in the DRN.
Evrard
A
A
INSERM U288, Neuropsychopharmacologie Moléculaire, Cellulaire et Fonctionnelle, Faculté de Médecine Pitié-Salpêtrière, 91 Boulevard de l'Hôpital, 75634 Paris Cedex 13, France. evrard@ext.jussieu.fr
Malagié
I
I
Laporte
A-M
AM
Boni
C
C
Hanoun
N
N
Trillat
A-C
AC
Seif
I
I
De Maeyer
E
E
Gardier
A
A
Hamon
M
M
Adrien
J
J
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D017660:Autoreceptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001921:Brain / Q000201:enzymology* / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D015283:Citalopram / Q000494:pharmacology; D015536:Down-Regulation / Q000235:genetics; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D008995:Monoamine Oxidase / Q000172:deficiency* / Q000235:genetics; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000201:enzymology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D014316:Tritium
D017660:Autoreceptors; D002352:Carrier Proteins; D015283:Citalopram; D006897:Hydroxyindoleacetic Acid; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008995:Monoamine Oxidase; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; 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; D014316:Tritium; C493231:Slc6a4 protein, mouse