PT  - JOURNAL ARTICLE
AU  - Emanuel Meller
AU  - Hua Li
AU  - Kenneth D. Carr
AU  - Jacob M. Hiller
TI  - 5-Hydroxytryptamine<sub>1A</sub> Receptor-Stimulated [<sup>35</sup>S]GTPγS Binding in Rat Brain: Absence of Regional Differences in Coupling Efficiency
DP  - 2000 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 684--691
VI  - 292
IP  - 2
4099  - http://jpet.aspetjournals.org/content/292/2/684.short
4100  - http://jpet.aspetjournals.org/content/292/2/684.full
SO  - J Pharmacol Exp Ther2000 Feb 01; 292
AB  - In hippocampal membranes, the selective 5-hydroxytryptamine (5-HT1A) receptor agonists 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) andN,N-dipropyl-5-carboxamidotryptamine (N,N-DP-5-CT) stimulated guanosine-5′-O-(3-thio)triphosphate ([35S]GTPγS) binding by 130 to 140%; binding stimulated by nonselective agonists (5-HT and 5-CT) was ∼30% greater. However, the selective 5-HT1A receptor antagonistN-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-cyclohexanecarboxamide (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-HT1A receptors [5-CT ≅ 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 thanR-(+)-8-OH-DPAT. R-(+)-8-OH-DPAT also stimulated [35S]GTPγS binding in cortex, but not in striatum, which lacks 5-HT1A receptors. Partial irreversible inactivation of 5-HT1A receptors, in vitro with phenoxybenzamine (0.3 or 1 μM) or in vivo withN-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (1 mg/kg), reduced the maximal response produced byR-(+)-8-OH-DPAT but did not alter its EC50. In autoradiographic sections, R-(+)-8-OH-DPAT stimulated [35S]GTPγS binding in 5-HT1A receptor-rich regions (dorsal hippocampus, 123%; lateral septum, 111%; midhippocampus, 110%; dorsal raphe nucleus, 83%; medial prefrontal cortex, ∼60%). The EC50 ofR-(+)-8-OH-DPAT did not vary significantly among brain regions (46–96 nM). Partial irreversible blockade of 5-HT1A receptors in brain sections (phenoxybenzamine, 10 μM) reduced the maximal response without altering the EC50 in both the hippocampus and dorsal raphe. Despite prior evidence that dorsal raphe somatodendritic 5-HT1Aautoreceptors 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. The American Society for Pharmacology and Experimental Therapeutics