5-Hydroxytryptamine(1A) receptor-stimulated [S-35]GTP gamma S binding in rat brain: Absence of regional differences in coupling efficiency

In hippocampal membranes, the selective 5-hydroxytryptamine (5-HT1A) recept or agonists 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) and N,N-dipropyl-5- carboxamidotryptamine (N,N-DP-5-CT) stimulated guanosine-5'-O-(3-thio)triph osphate ([S-35]GTP gamma S) binding by 130 to 140%; binding stimulated by n onselective agonists (5-HT and 5-CT) was similar to 30% greater. However, t he selective 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperaz inyl]ethyl]-N-2-pyridinyl-cyclohexanecarboxamide (WAY100,635) completely ab olished the increases produced by 8-OH-DPAT and N,N-DP-5-CT but only elimin ated 70% of that elicited by 5-CT. The rank potency order of the tested ago nists was identical with their rank order of affinity for 5-HT1A receptors [5-CT congruent to N,N-DP-5-CT > R-(+)-8-OH-DPAT > 5-HT > ipsapirone]. Race mic 8-OH-DPAT and the partial agonist ipsapirone exhibited lower intrinsic activity than R-(+)-8-OH-DPAT. R-(+)-8-OH-DPAT also stimulated [S-35]GTP ga mma S binding in cortex, but not in striatum, which lacks 5-HT1A receptors. Partial irreversible inactivation of 5-HT1A receptors, in vitro with pheno xybenzamine (0.3 or 1 mu M) or in vivo with N-ethoxycarbonyl-2-ethoxy-1,2-d ihydroquinoline (1 mg/kg), reduced the maximal response produced by R-(+)-8 -OH-DPAT but did not alter its EC50. In autoradiographic sections, R-(+)-8- OH-DPAT stimulated [S-35]GTP gamma S binding in 5-HT1A receptor-rich region s (dorsal hippocampus, 123%; lateral septum, 111%; midhippocampus, 110%; do rsal raphe nucleus, 83%; medial prefrontal cortex, similar to 60%). The EC5 0 of R-(+)-8-OH-DPAT did not vary significantly among brain regions (46-96 nM). Partial irreversible blockade of 5-HT1A receptors in brain sections (p henoxybenzamine, 10 mu M) reduced the maximal response without altering the EC50 in both the hippocampus and dorsal raphe. Despite prior evidence that dorsal raphe somatodendritic 5-HT1A autoreceptors exhibit high receptor/ef fector coupling efficiency (receptor reserve) compared with postsynaptic re ceptors in hippocampus, there was no evidence of a difference at the level of receptor/G protein coupling.