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

J Neurochem. 2001 Aug;78(3):619-30. doi: 10.1046/j.1471-4159.2001.00437.x.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8-Hydroxy-2-(di-n-propylamino)tetralin / metabolism
  • Animals
  • Autoradiography
  • Behavior, Animal / physiology
  • Brain / metabolism*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Citalopram / metabolism
  • Female
  • Immunohistochemistry
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Membrane Transport Proteins*
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins*
  • Neurons / cytology
  • Neurons / metabolism*
  • Pindolol / analogs & derivatives*
  • Pindolol / metabolism
  • Radioligand Assay
  • Receptor, Serotonin, 5-HT1B
  • Receptors, Serotonin / genetics
  • Receptors, Serotonin / metabolism*
  • Receptors, Serotonin, 5-HT1
  • Selective Serotonin Reuptake Inhibitors / metabolism
  • Serotonin / metabolism*
  • Serotonin Antagonists / metabolism
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Receptor Agonists / metabolism

Substances

  • Carrier Proteins
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Receptor, Serotonin, 5-HT1B
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT1
  • Serotonin Antagonists
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Receptor Agonists
  • Serotonin Uptake Inhibitors
  • Slc6a4 protein, mouse
  • Citalopram
  • Serotonin
  • cyanopindolol
  • 8-Hydroxy-2-(di-n-propylamino)tetralin
  • Pindolol