AUTORADIOGRAPHIC CHARACTERIZATION AND LOCALIZATION OF 5-HT(1D) COMPARED TO 5-HT(1B) BINDING-SITES IN RAT-BRAIN

The regional distribution and the pharmacology of the binding sites la belled with the novel 5-hydroxytryptamine (serotonin) 5-HT1B/1D select ive radioligand otonin-O-carboxy-methyl-glycyl-[I-125]tyrosinamide (ab breviated [I-125]GTI for the sake of simplicity) was determined using quantitative autoradiography in rat brain. The distribution of [I-125] GTI binding sites was largely comparable to that of [I-125]iodocyanopi ndolol ([I-125] ICYP) which labels 5-HT1B binding sites (in the presen ce of 8-OH-DPAT (8-hydroxy-[2N-dipropylamino]tetralin) and isoprenalin e, to prevent binding to 5-HT1A and beta-adrenoceptor binding sites), although a detailed analysis revealed differences. The pharmacology of the [I-125]GTI binding sites was analysed using compounds known to di splay high affinity for and/or distinguish between 5-HT1B and 5-HT1D s ites: 5-carboxamidotryptamine (5-CT), sumatriptan, CP 93129 droxy-3(4- 1,2,5,6-tetrahydropyridyl)-4-azaindole), (-)pindolol, PAPP (4[2-[4-[3- (trifluoromethyl) phenyl]-1-piperazinyl]ethyl]benzeneamine), rauwolsci ne, and 8-OH-DPAT. The displacement of [I-125]GTI by 5-CT was monophas ic. By contrast, the selective 5-HT1B compound CP 93129 and (-)pindolo l produced biphasic curves showing a majority of high affinity sites i n the globus pallidus and the substantia nigra, whereas PAPP and sumat riptan (which are somewhat 5-HT1D selective) produced biphasic curves indicating a minority of high affinity sites in these areas. In additi on, by blocking the 5-HT1B sites with 100 nM CP 93129, the remaining p opulation of [I-125]GTI binding sites could be studied and was found t o have high affinity for PAPP, rauwolscine and 8-OH-DPAT. The pharmaco logical profile of the major binding component was typical of the 5-HT 1B type: 5-CT>CP 93129 greater-than-or-equal-to (-)pindolol>sumatripta n greater-than-or-equal-to PAPP >rauwolscine. The profile of the minor component of [I-125]GTI binding is best characterised as that of a 5- HT1D site: 5-CT>PAPP greater-than-or-equal-to sumatriptan>rauwolscine > (-)pindolol greater-than-or-equal-to CP 93129. The localisation of t he non 5-HT1B [I-125]GTI binding sites was characterised by blocking t he 5-HT1B receptors with 100 nM CP 93129. Low densities of the 5-HT1D recognition sites were found to be present in globus pallidus, ventral pallidum, caudate-putamen, subthalamic nucleus, entopeduncular nucleu s, substantia nigra (reticular part), nuclei of the (normal and access ory) optic tract, different nuclei of the geniculate body and frontopa rietal cortex, although higher densities of 5-HT1B sites were always o bserved in the same structures. Thus, in agreement with the recent clo ning of a rat 5-HT1Dalpha receptor cDNA, the presence and the distribu tion of 5-HT1D sites could be documented in rat brain. However, when c ompared to 5-HT1B sites, 5-HT1D sites represent only a minor component of the [I-125]GTI binding in the rat brain structures studied.