title: 5-Hydroxytryptamine(1A) receptor-stimulated [(35)S]GTPgammaS binding in rat brain: absence of regional differences in coupling efficiency.
abstract: In hippocampal membranes, the selective 5-hydroxytryptamine (5-HT(1A)) receptor agonists 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) and N,N-dipropyl-5-carboxamidotryptamine (N,N-DP-5-CT) stimulated guanosine-5'-O-(3-thio)triphosphate ([(35)S]GTPgammaS) binding by 130 to 140%; binding stimulated by nonselective agonists (5-HT and 5-CT) was approximately 30% greater. However, the selective 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-cyclohex anecarboxamide (WAY100,635) completely abolished the increases produced by 8-OH-DPAT and N,N-DP-5-CT but only eliminated 70% of that elicited by 5-CT. The rank potency order of the tested agonists was identical with their rank order of affinity for 5-HT(1A) receptors [5-CT congruent with N,N-DP-5-CT > R-(+)-8-OH-DPAT > 5-HT > ipsapirone]. Racemic 8-OH-DPAT and the partial agonist ipsapirone exhibited lower intrinsic activity than R-(+)-8-OH-DPAT. R-(+)-8-OH-DPAT also stimulated [(35)S]GTPgammaS binding in cortex, but not in striatum, which lacks 5-HT(1A) receptors. Partial irreversible inactivation of 5-HT(1A) receptors, in vitro with phenoxybenzamine (0.3 or 1 microM) or in vivo with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (1 mg/kg), reduced the maximal response produced by R-(+)-8-OH-DPAT but did not alter its EC(50). In autoradiographic sections, R-(+)-8-OH-DPAT stimulated [(35)S]GTPgammaS binding in 5-HT(1A) receptor-rich regions (dorsal hippocampus, 123%; lateral septum, 111%; midhippocampus, 110%; dorsal raphe nucleus, 83%; medial prefrontal cortex, approximately 60%). The EC(50) of R-(+)-8-OH-DPAT did not vary significantly among brain regions (46-96 nM). Partial irreversible blockade of 5-HT(1A) receptors in brain sections (phenoxybenzamine, 10 microM) reduced the maximal response without altering the EC(50) in both the hippocampus and dorsal raphe. Despite prior evidence that dorsal raphe somatodendritic 5-HT(1A) autoreceptors exhibit high receptor/effector coupling efficiency (receptor reserve) compared with postsynaptic receptors in hippocampus, there was no evidence of a difference at the level of receptor/G protein coupling.
authors.affiliation: Millhauser Laboratories, Department of Psychiatry, New York University Medical Center, New York, New York, USA. emanuel.meller@med.nyu.edu
authors.forename: E
authors.initials: E
authors.lastname: Meller
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.forename: K D
authors.initials: KD
authors.lastname: Carr
authors.forename: J M
authors.initials: JM
authors.lastname: Hiller
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D010643:Phenoxybenzamine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding; D011725:Pyridines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D014363:Tryptamines / Q000494:pharmacology
chemical_list: D010879:Piperazines; D011725:Pyridines; D011804:Quinolines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; D010643:Phenoxybenzamine; D012701:Serotonin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C000470:EEDQ; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; C055895:N,N-dipropylcarboxamidotryptamine; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C047087:5-carboxamidotryptamine