EVALUATION OF 3 TRANSPORTER LIGANDS AS QUANTITATIVE MARKERS OF SEROTONIN INNERVATION DENSITY IN RAT-BRAIN

Direct counting of axon terminals (varicosities) labeled by uptake/sto rage of a tritiated monoamine provides a means to test radioligands of the corresponding membrane transporter as quantitative markers of reg ional monoamine innervation density in brain tissue. In autoradiograph s from alternate rat brain slices, counts of [H-3]5-HT-labeled axon te rminals were matched with densitometric measurements of the specific b inding of tritiated cyanoimipramine (CYI), citalopram (CITAL), and 6-n itroquipazine (6-NTQ), under conditions of hypo-, normo-, or hyper-5-H T innervation of the neostriatum. A total of 267 pairs of data were su bjected to a multilevel analysis (iterative generalized least square p rocedure). With all three ligands, there was a linear relationship bet ween the density of 5-HT innervation and the density of specific bindi ng 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 o f down- or up-regulation of the 5-HT transporter consequent to 5-HT hy po- 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 ha d 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 a s quantitative markers of 5-HT innervation density, at least in vitro, whereas 6-NTQ demonstrates a certain lack of specificity and sensitiv ity. Further work will be needed to assess the potential of CYI and CI TAL for positron emission tomographic studies of living brain. Such em pirical testing should also be applicable for screening radioligands o f the dopamine or the noradrenaline transporters. (C) 1995 Wiley-Liss, Inc.