Effects of tryptophan depletion on the binding of [11C]-DASB to the serotonin transporter in baboons: response to acute serotonin deficiency.
BACKGROUND
The objective of this study was to evaluate the sensitivity of [(11)C]-N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine (DASB) binding to the brain serotonin transporter (SERT) to changes in endogenous serotonin (5-hydroxytryptamine [5-HT]) levels. A ligand sensitive to endogenous competition (EC) would enable the measurement of fluctuations of intrasynaptic 5-HT. A ligand insensitive to EC can provide a measure of SERT unaffected by levels of 5-HT. Alternatively, serotonin depletion could accelerate internalization of SERT and reduce binding.


METHODS
Eighteen (14 baseline and 9 tryptophan-depleted) positron emission tomography (PET) scans were carried out in two baboons (Papio anubis). A metabolite-corrected arterial input function was used to estimate the binding potential (BP = B(max)/K(D)).


RESULTS
Depletion of plasma tryptophan by a mean of 65% from the baseline (p = .03) reduces [(11)C]-DASB BP in the six brain regions of interest (ROI). Lower DASB binding correlated with lower plasma tryptophan levels in the ROIs with higher SERT density.


CONCLUSIONS
[(11)C]-DASB binding to SERT in vivo rapidly declines in response to acute reduction in serotonin availability, contrary to what is predicted by a simple competition model. This rapid reduction in SERT availability may be due to accelerated transporter internalization.
Milak
Matthew S
MS
Department of Neuroscience, New York State Psychiatric Institute, Columbia University, 1051 Riverside Drive, New York, NY 10032, USA. mm2354@columbia.edu
Ogden
R Todd
RT
Vinocur
Daniel N
DN
Van Heertum
Ronald L
RL
Cooper
Thomas B
TB
Mann
J John
JJ
Parsey
Ramin V
RV
D000818:Animals; D001596:Benzylamines / Q000494:pharmacology*; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D001931:Brain Mapping; D002247:Carbon Isotopes; D008279:Magnetic Resonance Imaging / Q000379:methods; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism*; D010215:Papio; D049268:Positron-Emission Tomography / Q000379:methods; D011485:Protein Binding / Q000187:drug effects* / Q000502:physiology; D015203:Reproducibility of Results; D012701:Serotonin / Q000172:deficiency*; D050486:Serotonin Plasma Membrane Transport Proteins; D014018:Tissue Distribution; D014364:Tryptophan / Q000097:blood / Q000172:deficiency*
D001596:Benzylamines; D002247:Carbon Isotopes; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; C420885:N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D014364:Tryptophan