Distribution of S(−)-zacopride-insensitive []R(+)-zacopride binding sites in the rat brain and peripheral tissues

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• 作者：Ge ; Jian ; Barnes ; Janine M. ; Towers ; Patrick ; Barnes ; Nicholas M.
• 关键词：[¹²⁵I]R(+)-Zacopride ; Autoradiography ; Radioligand binding ; R(+)-site ; Brain ; rat ; Peripheral tissues ; rat
• 刊名：European Journal of Pharmacology
• 出版年：1997
• 出版时间：August 13, 1997
• 年：1997
• 卷：332
• 期：3
• 页码：307-312
• 全文大小：556 K

文摘

Increasing evidence indicates that the 5-HT₃ receptor antagonist R(+)-zacopride labels an additional site in brain tissue that is not sensitive to 5-HT (non-5-HT R(+)-zacopride site, R(+)-site). Since the levels of R(+)-sites in the brain are relatively low, the present studies explored the use of []R(+)-zacopride to label the R(+)-site; the incorporation of an [] atom considerably increasing the specific activity of the radioligand relative to []R(+)-zacopride that has been utilised previously. Competition experiments with []R(+)-zacopride (1.0 nM) binding to rat whole brain homogenates, in the presence of the 5-HT₃ receptor antagonist granisetron (1.0 μM), identified that R(+)-zacopride and prazosin bound to two sites (pIC₅₀: 7.59 and 5.28, respectively, for R(+)-zacopride; 6.75 and 4.42, respectively, for prazosin) whereas S(−)-zacopride and mianserin possessed relatively low affinity (pIC₅₀: 4.37 and 3.80, respectively) while (−)sulpiride and 5-HT failed to compete for []R(+)-zacopride binding at concentrations up to 10 μM. Autoradiographic radioligand binding studies using []R(+)-zacopride (0.5 nM) identified a heterogeneous distribution of specific binding sites (defined by unlabelled R(+)-zacopride, 1.0 μM) throughout the rat brain. In the presence of a saturating concentration of granisetron (1.0 μM), highest levels of specific []R(+)-zacopride binding sites (defined by R(+)-zacopride, 1.0 μM; R(+)-site), were detected in the olfactory tubercle, thalamus, corpus callosum, colliculus, dorsal and median raphe nucleus, spinal cord and the pons (8.0–13.0 fmol/mg). Moderate densities of R(+)-sites were located in the striatum, nucleus accumbens, substantia nigra, ventral tegmental area, globus pallidus, septal nuclei, frontal cortex and cerebellum (2.0–7.9 fmol/mg). In the hippocampus, amygdala and cortical areas, R(+)-site levels were low but detectable (0.1–1.9 fmol/mg). []R(+)-zacopride labelled R(+)-sites were also detected in some rat peripheral tissues, for instance kidney cortex, adrenal gland and liver (2.4–6.8 fmol/mg). The present results indicate that specific non-5-HT []R(+)-zacopride sites are heterogeneously distributed throughout the rat brain and are expressed in various peripheral tissues.