Norepinephrine transporter knockout-induced up-regulation of brain alpha2A/C-adrenergic receptors.
The norepinephrine transporter (NET) is responsible for the rapid removal of norepinephrine released from sympathetic neurons; this release is controlled by inhibitory alpha(2)-adrenergic receptors (alpha(2)ARs). Long-term inhibition of the NET by antidepressants has been reported to change the density and function of pre- and postsynaptic ARs, which may contribute to the antidepressant effects of NET inhibitors such as desipramine. NET-deficient (NET-KO) mice have been described to behave like antidepressant-treated mice. By means of quantitative real-time PCR we show that mRNAs encoding the alpha(2A)-adrenergic receptor (alpha(2A)AR) and the alpha(2C)-adrenergic receptor (alpha(2C)AR) are up-regulated in the brainstem, and that alpha(2C)AR mRNA is also elevated in the hippocampus and striatum of NET-KO mice. These results were confirmed at the protein level by quantitative autoradiography. The NET-KO mice showed enhanced binding of the selective alpha(2)AR antagonist [(3)H]RX821002 in several brain regions. Most robust increases (20-25%) in alpha(2)AR expression were observed in the hippocampus and in the striatum. Significant increases (16%) were also seen in the extended amygdala and thalamic structures. In an 'in vivo' test, the alpha(2)AR agonist clonidine (0.1 mg/kg) caused a significantly greater reduction of locomotor activity in NET-KO mice than in wild-type mice, showing the relevance of our findings at the functional level.
Gilsbach
R
R
Institute of Pharmacology & Toxicology, University of Bonn, Germany.
Faron-Górecka
A
A
Rogóz
Z
Z
Brüss
M
M
Caron
M G
MG
Dziedzicka-Wasylewska
M
M
Bönisch
H
H
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000502:physiology*; D003000:Clonidine / Q000494:pharmacology; D017931:DNA Primers; D019329:Idazoxan / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000235:genetics*
D000317:Adrenergic alpha-Antagonists; D017931:DNA Primers; D050484:Norepinephrine Plasma Membrane Transport Proteins; D012333:RNA, Messenger; D018341:Receptors, Adrenergic, alpha-2; C058525:2-methoxyidazoxan; D003000:Clonidine; D019329:Idazoxan