LY334370: Unraveling its G-Protein Activation at 5-HT1A Receptors in Guinea Pig Brain and Recombinant Cell Lines

The study explored the activation of G-proteins by the 5-HT1F receptor agonist LY334370 in guinea-pig brain sections and cell lines expressing human 5-HT1A receptors. Autoradiography and [35S]-GTPγS binding responses were used to assess the agonist's activity.

In guinea-pig brain regions known for 5-HT1F binding sites, LY334370 did not stimulate [35S]-GTPγS binding. However, when applied to brain sections, it increased [35S]-GTPγS binding in areas such as the hippocampus, lateral septum, dorsal raphe, entorhinal, and cingulate cortex—regions associated with 5-HT1A receptor-mediated G-protein activation. The agonist's effect was blocked by the selective 5-HT1A receptor antagonist WAY100635, suggesting that LY334370-induced response in guinea-pig brain is indeed mediated by 5-HT1A receptors.

The maximal [35S]-GTPγS binding response induced by LY334370 in recombinant C6-glial/h 5-HT1A and HeLa/h 5-HT1A cells was similar to that of 5-HT, indicating high intrinsic activity of LY334370 at h 5-HT1A receptors.

The findings conclude that LY334370 induces G-protein activation in guinea-pig brain sections and recombinant cell lines through 5-HT1A receptors, not 5-HT1F as initially presumed. This indicates that caution should be exercised when using LY334370 as a selective 5-HT1F agonist.