Receptor mediation of exaggerated responses to serotonin-enhancing drugs in serotonin transporter (SERT)-deficient mice

Neuropharmacology. 2007 Oct;53(5):643-56. doi: 10.1016/j.neuropharm.2007.07.009. Epub 2007 Jul 27.


Administration of serotonin-enhancing drugs induces a distinctive behavioral syndrome in rodents. We previously reported that mice with a targeted disruption of the serotonin transporter (SERT) display some of these behaviors spontaneously, in the absence of drug. In the current studies, we assessed the drug-induced serotonin syndrome in SERT wildtype (+/+), heterozygous (+/-) and knockout (-/-) mice. In SERT -/- mice, the monoamine oxidase inhibitor (MAOI) tranylcypromine (1mg/kg) or the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP; 80 mg/kg) led to markedly exaggerated serotonin syndrome behaviors relative to SERT +/+ mice, with an intermediate phenotype in SERT +/- mice. SERT +/+ mice developed significant serotonin syndrome behaviors only with the combination of the MAO-A/B inhibitor tranylcypromine (0.5 or 1 mg/kg) or the MAO-A-selective inhibitor clorgyline (1.2 mg/kg) plus 5-HTP. In evaluations of underlying mechanisms, pretreatment with the Htr1a receptor antagonist WAY 100635 (1 mg/kg), but not the Htr7 antagonist SB 269970 (3 mg/kg) or the Htr2a antagonist MDL 11,939 (5 mg/kg), markedly decreased the exaggerated 5-HTP-induced behaviors in SERT -/- mice. Subsequent experiments showed that the Htr1a agonist 8-OH-DPAT (1 or 2 mg/kg) elicited serotonin syndrome behaviors in a dose-dependent manner, blocked by WAY 100635 (1 mg/kg), in mice of all three genotypes, confirming the role of Htr1a receptors. The current data document markedly enhanced behavioral sensitivity to serotonin-enhancing drugs in SERT-deficient mice. These studies also show that the exaggerated behavioral responses observed in SERT +/- and -/- mice are mediated by postsynaptic Htr1a receptors, and suggest intact postsynaptic Htr1a function in SERT -/- mice.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • 5-Hydroxytryptophan / pharmacology
  • 8-Hydroxy-2-(di-n-propylamino)tetralin / pharmacology
  • Animals
  • Behavior, Animal / drug effects
  • Dose-Response Relationship, Drug
  • Female
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monoamine Oxidase Inhibitors / pharmacology
  • Piperazines / pharmacology
  • Piperidines / pharmacology
  • Polymorphism, Genetic / genetics
  • Pyridines / pharmacology
  • Receptors, Serotonin / drug effects*
  • Serotonin Antagonists / pharmacology
  • Serotonin Plasma Membrane Transport Proteins / deficiency*
  • Serotonin Plasma Membrane Transport Proteins / genetics*
  • Serotonin Receptor Agonists / pharmacology*
  • Serotonin Syndrome / psychology
  • Tranylcypromine / pharmacology


  • Monoamine Oxidase Inhibitors
  • Piperazines
  • Piperidines
  • Pyridines
  • Receptors, Serotonin
  • Serotonin Antagonists
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Receptor Agonists
  • alpha-phenyl-1-(2-phenylethyl)-4-piperidinemethanol
  • Tranylcypromine
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
  • 8-Hydroxy-2-(di-n-propylamino)tetralin
  • 5-Hydroxytryptophan