Impaired Activity of the Extraneuronal Monoamine Transporter System Known as Uptake-2 in Orct3/Slc22a3-Deficient Mice

Abstract

Two uptake systems that control the extracellular concentrations of released monoamine neurotransmitters such as noradrenaline and adrenaline have been described. Uptake-1 is present at presynaptic nerve endings, whereas uptake-2 is extraneuronal and has been identified in myocardium and vascular and nonvascular smooth muscle cells. The gene encoding the uptake-2 transporter has recently been identified in humans (EMT), rats (OCT3), and mice (Orct3/Slc22a3). To generate an in vivo model for uptake-2, we have inactivated the mouse Orct3 gene. Homozygous mutant mice are viable and fertile with no obvious physiological defect and also show no significant imbalance of noradrenaline or dopamine. However, Orct3-null mice show an impaired uptake-2 activity as measured by accumulation of intravenously administered [ H]MPP ؉ (1-methyl-4-phenylpyridinium). A 72% reduction in MPP؉ levels was measured in hearts of both male and female Orct3 mutant mice. No significant differences between wild-type and mutant mice were found in any other adult organ or in plasma. When [ 3 H]MPP ؉ was injected into pregnant females, a threefold-reduced MPP ؉ accumulation was observed in homozygous mutant embryos but not in their placentas or amniotic fluid. These data show that Orct3 is the principal component for uptake-2 function in the adult heart and identify the placenta as a novel site of action of uptake-2 that acts at the fetoplacental interface.

Decynium-22 Enhances SSRI-Induced Antidepressant-Like Effects in Mice: Uncovering Novel Targets to Treat Depression

“…Adult (Ͼ60-d-old; 25-30 g) male C57BL/6 mice, or OCT3 knock-out (KO) mice (bred on a C57BL/6 background, originally developed by Zwart et al (2001) and generously provided to us by Drs. Kim Tieu, Bruno Giros, and Sophie Gautron) were used for all experiments.…”

Taste of a Pill

“…Animals-The Oct3 (Slc22a3) null mice of the FVB inbred strain were originally developed by Dr. Denise Barlow (15) and maintained by Dr. Alfred Schinkel (Netherlands Cancer Institute). After re-derivation at Charles River Laboratories (16), breeding pairs of Oct3 ϩ/ϩ and Oct3 Ϫ/Ϫ mice were kindly provided to us by Dr. John Markowitz (University of Florida) with approval from Dr. Schinkel.…”

Imprinted genes in mouse placental development and the regulation of fetal energy stores

“…Slc22a3 null mice are viable and fertile with no overt placental defect (Zwart et al 2001b, Jonker et al 2003.…”