title: Differential sensitivity of 3H-agonist binding to pre- and postsynaptic 5-HT1A receptors in bovine brain.
abstract: 1. The full and weak partial 5-HT1A agonist ligands [3H]-8-OH-DPAT and [3H]-BMY-7378 were used to characterize the binding parameters of pre- and postsynaptic 5-HT1A binding sites in bovine dorsal raphe and hippocampal membranes, respectively. The Kd and Bmax values for the individual radioligands were indistinguisable across the regions tested, as were the Ki values generated by a series of agents acting at 5-hydroxytryptamine (5-HT) receptors. 2. The concentration-dependent allosteric attenuation of [3H]-8-OH-DPAT and [3H]-BMY-7378 binding produced by the nonhydrolyzable guanyl nucleotide, Gpp(NH)p, generated similar IC50 values within a particular region; however, these were significantly different between regions. While the maximal attenuation of [3H]-8-OH-DPAT and [3H]-BMY-7378 binding was similar in dorsal raphe, Gpp(NH)p produced a significantly greater attenuation of [3H]-8-OH-DPAT binding in hippocampal membranes when compared to [3H]-BMY-7378. The maximal attenuation of [3H]-8-OH-DPAT binding by Gpp(NHp) in hippocampus was also significantly greater than that seen with either radioligand in dorsal raphe. 3. Although exposure to Gpp(NH)p had no effect on the affinity constants of either radioligand in either region, it produced a concentration-dependent reduction in the maximal number of binding sites for both radioligands in both regions. While the percentage reduction in Bmax values were similar for both radioligands in the dorsal raphe, Gpp(NH)p reduced the Bmax of [3H]-8-OH-DPAT in hippocampus significantly more than that of [3H]-BMY-7378. 4. These results suggest that while pre- and postsynaptic 5-HT1A receptors may share similar pharmacological recognition properties, a region-dependent difference in the coupling of the 5-HT1A receptor to G-proteins may exist.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT 06492.
authors.forename: L G
authors.initials: LG
authors.lastname: Iben
authors.forename: C D
authors.initials: CD
authors.lastname: Mahle
authors.forename: F D
authors.initials: FD
authors.lastname: Yocca
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002417:Cattle; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D010879:Piperazines / Q000494:pharmacology; D011869:Radioligand Assay; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017661:Receptors, Presynaptic / Q000187:drug effects / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000378:metabolism*
chemical_list: D010879:Piperazines; D017661:Receptors, Presynaptic; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D006165:Guanylyl Imidodiphosphate; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C053428:BMY 7378