Evaluation of three transporter ligands as quantitative markers of serotonin innervation density in rat brain.
Direct counting of axon terminals (varicosities) labeled by uptake/storage of a tritiated monoamine provides a means to test radioligands of the corresponding membrane transporter as quantitative markers of regional monoamine innervation density in brain tissue. In autoradiographs from alternate rat brain slices, counts of [3H]5-HT-labeled axon terminals were matched with densitometric measurements of the specific binding of tritiated cyanoimipramine (CYI), citalopram (CITAL), and 6-nitroquipazine (6-NTQ), under conditions of hypo-, normo-, or hyper-5-HT innervation of the neostriatum. A total of 267 pairs of data were subjected to a multilevel analysis (iterative generalized least square procedure). With all three ligands, there was a linear relationship between the density of 5-HT innervation and the density of specific binding and no change in the slope of the regression lines as a function of 5-HT innervation density. Thus, none of these ligands gave any sign of down- or up-regulation of the 5-HT transporter consequent to 5-HT hypo- or hyper-innervation. The regression lines for CYI and CITAL were not significantly different from one another and crossed the ordinate near zero, whereas the regression line for 6-NTQ was less steep and had a higher intercept with the ordinate. In addition, the dispersion of values around the regression line (residuals) was lower with CYI and CITAL than 6-NTQ. It was concluded that both CYI and CITAL may serve as quantitative markers of 5-HT innervation density, at least in vitro, whereas 6-NTQ demonstrates a certain lack of specificity and sensitivity. Further work will be needed to assess the potential of CYI and CITAL for positron emission tomographic studies of living brain. Such empirical testing should also be applicable for screening radioligands of the dopamine or the noradrenaline transporters.
Descarries
L
L
Département de Pathologie, Université de Montréal, Québec, Canada.
Soucy
J P
JP
Lafaille
F
F
Mrini
A
A
Tanguay
R
R
D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism*; D015283:Citalopram / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism / Q000648:ultrastructure; D003720:Densitometry; D007099:Imipramine / Q000031:analogs & derivatives* / Q000378:metabolism; D066298:In Vitro Techniques; D008024:Ligands; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D009411:Nerve Endings / Q000378:metabolism; D009419:Nerve Tissue Proteins; D011814:Quipazine / Q000031:analogs & derivatives* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins
D002352:Carrier Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; C024316:cianopramine; D015283:Citalopram; D012701:Serotonin; D011814:Quipazine; C031227:6-nitroquipazine; D007099:Imipramine