DISTRIBUTION OF S(-)-ZACOPRIDE-INSENSITIVE [I-125] R(-ZACOPRIDE BINDING-SITES IN THE RAT-BRAIN AND PERIPHERAL-TISSUES())

Increasing evidence indicates that the 5-HT3 receptor antagonist R(+)- zacopride labels an additional site in brain tissue that is not sensit ive to 5-HT (non-5-HT R(+)-zacopride site, R(+)-site). Since the level s of R(+)-sites in the brain are relatively low, the present studies e xplored the use of [I-125]R(+)-zacopride to label the R(+)-site; the i ncorporation of an [I-125] atom considerably increasing the specific a ctivity of the radioligand relative to [H-3]R(+)-zacopride that has be en utilised previously. Competition experiments with [I-125]R(+)-zacop ride (1.0 nM) binding to rat whole brain homogenates, in the presence of the 5-HT3 receptor antagonist granisetron (1.0 mu M), identified th at R(+)-zacopride and prazosin bound to two sites (pIC(50):7.59 and 5. 28, respectively, for R(+)-zacopride; 6.75 and 4.42, respectively, for prazosin) whereas S(-)-zacopride and mianserin possessed relatively l ow affinity (pIC(50): 4.37 and 3.80, respectively) while (-)sulpiride and 5-HT failed to compete for [I-125]R(+)-zacopride binding at concen trations up to 10 mu M. Autoradiographic radioligand binding studies u sing [I-125]R(+)-zacopride (0.5 nM) identified a heterogeneous distrib ution of specific binding sites (defined by unlabelled R(+)-zacopride, 1.0 mu M) throughout the rat brain. In the presence of a saturating c oncentration of granisetron (1.0 mu M), highest levels of specific [I- 125]R(+)-zacopride binding sites (defined by R(+)-zacopride, 1.0 mu M; R(+)-site), were detected in the olfactory tubercle, thalamus, corpus callosum, colliculus, dorsal and median raphe nucleus, spinal cord an d the pens (8.0-13.0 fmol/mg). Moderate densities of R(+)-sites were l ocated in the striatum, nucleus accumbens, substantia nigra, ventral t egmental area, globus pallidus, septal nuclei, frond cortex and cerebe llum (2.0-7.9 fmol/mg). In the hippocampus, amygdala and cortical area s, R(+)-site levels were low but detectable (0.1-1.9 fmol/mg). [I-125] R(+)-zacopride labelled R(+)-sites were also detected in some rat peri pheral tissues, for instance kidney cortex, adrenal gland and liver (2 .4-6.8 fmol/mg). The present results indicate that specific non-5-HT [ I-125]R(+)-zacopride sites are heterogeneously distributed throughout the rat brain and are expressed in various peripheral tissues. (C) 199 7 Elsevier Science B.V.