Autoradiographic characterisation and localisation of 5-HT1D compared to 5-HT1B binding sites in rat brain.
The regional distribution and the pharmacology of the binding sites labelled with the novel 5-hydroxytryptamine (serotonin) 5-HT1B/1D selective radioligand serotonin-O-carboxy-methyl-glycyl-[125I]tyrosinamide (abbreviated [125I]GTI for the sake of simplicity) was determined using quantitative autoradiography in rat brain. The distribution of [125I]GTI binding sites was largely comparable to that of [125I]iodocyanopindolol ([125I] ICYP) which labels 5-HT1B binding sites (in the presence of 8-OH-DPAT (8-hydroxy-[2N-dipropylamino]tetralin) and isoprenaline, to prevent binding to 5-HT1A and beta-adrenoceptor binding sites), although a detailed analysis revealed differences. The pharmacology of the [125I]GTI binding sites was analysed using compounds known to display high affinity for and/or distinguish between 5-HT1B and 5-HT1D sites: 5-carboxamidotryptamine (5-CT), sumatriptan, CP 93129 (5-hydroxy-3(4-1,2,5,6-tetrahydropyridyl)-4-azaindole), (-)pindolol, PAPP (4[2-[4-[3-(trifluoromethyl)phenyl]-1- piperazinyl]ethyl]benzeneamine), rauwolscine, and 8-OH-DPAT. The displacement of [125I]GTI by 5-CT was monophasic. By contrast, the selective 5-HT1B compound CP 93129 and (-)pindolol produced biphasic curves showing a majority of high affinity sites in the globus pallidus and the substantia nigra, whereas PAPP and sumatriptan (which are somewhat 5-HT1D selective) produced biphasic curves indicating a minority of high affinity sites in these areas. In addition, by blocking the 5-HT1B sites with 100 nM CP 93129, the remaining population of [125I]GTI binding sites could be studied and was found to have high affinity for PAPP, rauwolscine and 8-OH-DPAT. The pharmacological profile of the major binding component was typical of the 5-HT1B type: 5-CT > CP 93129 > or = (-)pindolol > sumatriptan > or = PAPP > rauwolscine. The profile of the minor component of [125I]GTI binding is best characterised as that of a 5-HT1D site: 5-CT > PAPP > or = sumatriptan > rauwolscine > (-)pindolol > or = CP 93129. The localisation of the non 5-HT1B [125I]GTI binding sites was characterised by blocking the 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 nucleus, substantia nigra (reticular part), nuclei of the (normal and accessory) optic tract, different nuclei of the geniculate body and frontoparietal cortex, although higher densities of 5-HT1B sites were always observed in the same structures.(ABSTRACT TRUNCATED AT 400 WORDS)
Bruinvels
A T
AT
Preclinical Research 360/604, Sandoz Pharma Ltd., Basel, Switzerland.
Palacios
J M
JM
Hoyer
D
D
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D003001:Cloning, Molecular; D004151:Dipeptides; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D020120:Iodocyanopindolol; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D010869:Pindolol / Q000031:analogs & derivatives; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000031:analogs & derivatives
D004151:Dipeptides; D007457:Iodine Radioisotopes; D011985:Receptors, Serotonin; C072128:serotonin-O-carboxymethyl-Gly-Tyr; D012701:Serotonin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D020120:Iodocyanopindolol; D010869:Pindolol; D007545:Isoproterenol