Regional changes in density of serotonin transporter in the brain of 5-HT1A and 5-HT1B knockout mice, and of serotonin innervation in the 5-HT1B knockout.
5-HT1A knockout (KO) mice display an anxious-like phenotype, whereas 5-HT1B KOs are over-aggressive. To identify serotoninergic correlates of these altered behaviors, autoradiographic measurements of 5-HT1A and 5-HT1B serotonin (5-HT) receptors and transporter (5-HTT) were obtained using the radioligands [3H]8-OH-DPAT, [125I]cyanopindolol and [3H]citalopram, respectively. By comparison to wild-type, density of 5-HT1B receptors was unchanged throughout brain in 5-HT1A KOs, and that of 5-HT1A receptors in 5-HT1B KOs. In contrast, decreases in density of 5-HTT binding were measured in several brain regions of both genotypes. Moreover, 5-HTT binding density was significantly increased in the amygdalo-hippocampal nucleus and ventral hippocampus of the 5-HT1B KOs. Measurements of 5-HT axon length and number of axon varicosities by quantitative 5-HT immunocytochemistry revealed proportional increases in the density of 5-HT innervation in these two regions of 5-HT1B KOs, whereas none of the decreases in 5-HTT binding sites were associated with any such changes. Several conclusions could be drawn from these results: (i) 5-HT1B receptors do not adapt in 5-HT1A KOs, nor do 5-HT1A receptors in 5-HT1B KOs. (ii) 5-HTT is down-regulated in several brain regions of 5-HT1A and 5-HT1B KO mice. (iii) This down-regulation could contribute to the anxious-like phenotype of the 5-HT1A KOs, by reducing 5-HT clearance in several territories of 5-HT innervation. (iv) The 5-HT hyperinnervation in the amygdalo-hippocampal nucleus and ventral hippocampus of 5-HT1B KOs could play a role in their increased aggressiveness, and might also explain their better performance in some cognitive tests. (v) These increases in density of 5-HT innervation provide the first evidence for a negative control of 5-HT neuron growth mediated by 5-HT1B receptors.
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Département de Physiologie, Centre de Recherche en Sciences Neurologiques, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada.
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D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D015283:Citalopram / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010869:Pindolol / Q000031:analogs & derivatives* / Q000378:metabolism; D011869:Radioligand Assay; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D002352:Carrier Proteins; D015283:Citalopram; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010869:Pindolol; 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; C493231:Slc6a4 protein, mouse; C047975:cyanopindolol