title: [3H]1-[2-(2-thienyl)cyclohexyl]piperidine labels two high-affinity binding sites in human cortex: further evidence for phencyclidine binding sites associated with the biogenic amine reuptake complex.
abstract: Previous work demonstrated two high-affinity PCP binding sites in guinea pig brain labeled by [3H]TCP (1-(1-[2-thienyl]cyclohexyl)piperidine): site 1 (N-methyl-D-aspartate [NMDA]-associated) and site 2 (dopamine-reuptake complex associated). The present study examined brain membranes prepared from various species, including human, for the presence of site 2, defined as binding in the presence of (+)-5-methyl-10,11-dihydro-5H-dibenzo [a, d]cyclohepten-5,10-imine maleate ((+)-MK801) minus binding in the presence of 10 microM TCP (nonspecific binding). Studies were conducted in absence of sodium which was found to be inhibitory to [3H]TCP binding. The results demonstrated detectable levels of site 2 in brain membranes of guinea pig, rabbit, pig, mouse, sheep, and human but not in the rat or chicken. Using human cortical membranes, site 2 was the predominant binding site. Detailed studies conducted with human cortical tissue showed that high-affinity dopamine (1-[2- [bis(4-fluorophenyl)-methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR12909)], [1,2]benzo(b)thiophenylcyclo-hexylpiperidine (BTCP), and serotonin (fluoxetine) uptake inhibitors produced a wash-resistant inhibition of [3H]TCP binding to site 2, but not site 1. Preincubation of guinea pig brain membranes with BTCP was shown to produce an increase in the dissociation rate of [3H]TCP from PCP site 2. Structure activity studies with various uptake inhibitors showed that GBR12909, benztropine, fluoxetine, and BTCP have higher affinity for site 2 than for site 1. (+)-MK801, ketamine, and tiletamine were very selective for site 1, whereas dexoxadrol and TCP were moderately selective for site 1. These results suggest that human cortex possesses high-affinity PCP binding sites associated with biogenic reuptake binding sites, and that guinea pig brain, but not rat brain, may be an appropriate animal model for studying PCP site 2 in human brain.
authors.affiliation: Unit on Receptor Studies, NIDDK, NIMH, Bethesda, Maryland 20892.
authors.forename: H C
authors.initials: HC
authors.lastname: Akunne
authors.forename: A A
authors.initials: AA
authors.lastname: Reid
authors.forename: A
authors.initials: A
authors.lastname: Thurkauf
authors.forename: A E
authors.initials: AE
authors.lastname: Jacobson
authors.forename: B R
authors.initials: BR
authors.lastname: de Costa
authors.forename: K C
authors.initials: KC
authors.lastname: Rice
authors.forename: M P
authors.initials: MP
authors.lastname: Heyes
authors.forename: R B
authors.initials: RB
authors.lastname: Rothman
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001667:Binding, Competitive; D001679:Biogenic Amines / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism*; D005473:Fluoxetine / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D051379:Mice; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D010622:Phencyclidine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011817:Rabbits; D012756:Sheep; D012965:Sodium Chloride / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013552:Swine; D014316:Tritium
chemical_list: D001679:Biogenic Amines; D014179:Neurotransmitter Uptake Inhibitors; D010879:Piperazines; D005473:Fluoxetine; D014316:Tritium; C056415:1-(1-(2-benzo(b)thienyl)cyclohexyl)piperidine; D012965:Sodium Chloride; C012058:tenocyclidine; C043425:vanoxerine; D010622:Phencyclidine