ADAM is an effective tool for in vivo study of serotonergic function: validation in rat models.
ADAM, 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine, is a recently described SPECT tracer for exploration of the serotonin transporter. We evaluated its potential to detect abnormalities in serotonergic function in the rat using 1) a model of serotonergic neuron lesion induced with 5,7-dihydroxytryptamine (5,7-DHT), and 2) experimental induction of acute decrease in endogenous brain serotonin levels. Cerebral biodistribution studies of [125I]ADAM were performed in normal conditions, in 5,7-DHT-lesioned rats, and after acute serotonin depletion obtained with p-chlorophenylalanine (pCPA). Around 50% reduction in accumulation of ADAM was observed in the hypothalamus and hippocampus 3 weeks after lesion of serotonergic neurons, whereas a more modest decrease of 15-30% occurred in the thalamus, frontal cortex, and striatum. This demonstrated the ability of the tracer to detect serotonergic neuron loss in vivo. After inducing acute 5-HT depletion with pCPA, we observed an increase in in vivo [125I]ADAM binding in all brain areas studied. The higher in vivo binding of [125I]ADAM in pCPA-treated rats than in controls was mainly due to an increase in specific binding to the SERT, as demonstrated by greatly reduced binding in the presence of a saturating dose of paroxetine. This may indicate in vivo competition between ADAM and 5-HT for binding to the SERT. The present findings thus demonstrate that ADAM is a specific SERT radioligand which can be used for in vivo study of central serotonin systems, and supports its use as a tracer for SPECT studies in human disorders involving dysfunction of serotonergic neurotransmission.
Chalon
Sylvie
S
INSERM U316, Laboratoire de Biophysique médicale et pharmaceutique, UFR des Sciences Pharmaceutiques, 37200 Tours, France. chalon@univ-tours.fr
Bronquard
Cécile
C
Vercouillie
Johnny
J
Kodas
Ercem
E
Garreau
Lucette
L
Bodard
Sylvie
S
Emond
Patrick
P
Besnard
Jean-Claude
JC
Guilloteau
Denis
D
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002352:Carrier Proteins; D002928:Cinanserin / Q000031:analogs & derivatives*; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011849:Radioactive Tracers; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000172:deficiency / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins
C413491:2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011849:Radioactive Tracers; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D012701:Serotonin; D002928:Cinanserin