Serotonergic binding in the rat dorsal raphe nucleus: critical role of MAO inhibition.
The biochemical properties of the 5-HT1A receptor in dorsal raphe nucleus (DRN) were investigated using a micropunch procedure. Initially, the Ki value for 5-hydroxytryptamine (5-HT) binding to a site labeled by the 5-HT1A-selective ligand [3H]8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was 20-fold higher than the KD for [3H]5-HT. In addition, a number of putative 5-HT1A selective ligands displayed poor affinity for the [3H]8-OH-DPAT site. The possibility that these discrepant results were due to metabolism of the receptor ligands was investigated by increasing the concentration of the monoamine oxidase (MAO) inhibitor, pargyline. Increasing the concentration of pargyline reduced, but did not abolish, the discrepancy between the Ki and KD values for 5-HT. However, inclusion of clorgyline, which is a more potent MAO inhibitor, resulted in an-excellent agreement between the Ki and KD values for 5-HT. In addition, when clorgyline was used, 5-HT1A-selective compounds displayed high affinity for the DRN binding site consistent with [3H]8-OH-DPAT labeling a 5-HT1A receptor in this tissue. The present study describes a fast and easy method for measuring biochemical properties in small discrete brain areas. These studies also indicate that pargyline should be replaced in serotonergic binding assays with a more potent inhibitor of monoamine oxidase such as clorgyline.
Department of Pharmacology, SUNY-Buffalo, USA.
R G
RG
Johnson
C M
CM
Severin
R A
RA
Rabin
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D008996:Monoamine Oxidase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D010293:Pargyline / Q000378:metabolism / Q000494:pharmacology*; D011903:Raphe Nuclei / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists / Q000378:metabolism* / Q000494:pharmacology
D008996:Monoamine Oxidase Inhibitors; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D010293:Pargyline