Autoradiography of Serotonin 5‐HT1A Receptor‐Activated G Proteins in Guinea Pig Brain Sections by Agonist‐Stimulated [35S]GTPγS Binding

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Abstract
G protein activation mediated by serotonin 5‐HT1A and 5‐HT1B/D receptors in guinea pig brain was investigated by using quantitative autoradiography of agonist‐stimulated [35S]GTPγS binding to brain sections. [35S]GTPγS binding was stimulated by the mixed 5‐HT1A/5‐HT1B/D agonist L694247 in brain structures enriched in 5‐HT1A binding sites, i.e., hippocampus (+140 ± 14%), dorsal raphe (+70 ± 8%), lateral septum (+52 ± 12%), cingulate (+36 ± 8%), and entorhinal cortex (+34 ± 5%). L694247 caused little or no stimulation of [35S]GTPγS binding in brain regions with high densities of 5‐HT1B/D binding sites (e.g., substantia nigra, striatum, central gray, and dorsal subiculum). The [35S]GTPγS binding response was antagonized by WAY100635 (10 µM) and methiothepin (10 µM). In contrast, the 5‐HT1B inverse agonist SB224289 (10 µM) did not affect the L694247‐mediated [35S]GTPγS binding response, and the mixed 5‐HT1B/D antagonist GR127935 (10 µM) yielded a partial blockade. The distribution pattern of the [35S]GTPγS binding response and the antagonist profile suggest the L694247‐mediated response in guinea pig brain to be mediated by 5‐HT1A receptors. In addition to L694247, 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin, and flesinoxan also stimulated [35S]GTPγS binding; their maximal responses varied between 46 and 52% compared with L694247, irrespective of the brain structure being considered. Sumatriptan, rizatriptan, and zolmitriptan (10 µM) stimulated [35S]GTPγS binding in the hippocampus by 20–50%. Naratriptan, CP122638, and dihydroergotamine stimulated [35S]GTPγS binding to a similar level as L694247 in hippocampus, lateral septum, and dorsal raphe. It appears that under the present experimental conditions, G protein activation through 5‐HT1A but not 5‐HT1B/D receptors can be measured in guinea pig brain sections.

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