Serotonin 5-HT 1A receptor biased agonists induce different cerebral metabolic responses: A [ 18 F]FDG PET study in conscious and anesthetized rats

Elise Levigoureux, Benjamin Vidal, Sylvain Fieux, Caroline Bouillot, Stéphane Emery, Adrian Newman-Tancredi, Luc Zimmer
ACS Chemical Neuroscience 2018 December 21
Serotonin 5-HT1A receptors constitute an attractive therapeutic target for various psychiatric or neurodegenerative disorders. These receptors are expressed in multiple brain regions on different neuronal populations, and can be coupled with distinct G-protein subtypes; such functional diversity complicates the use of 5-HT1A ligands in several pathologies where it would be desirable to stimulate the receptors in a precise region. Therefore, using "biased agonists" able to target specifically certain subpopulations of 5-HT1A receptors would enable to achieve a better therapeutic benefit. Several 5-HT1A receptor biased agonists are currently in development, including NLX-101 (a.k.a. F15599) and NLX-112 (a.k.a. F13640, befiradol), with preclinical data suggesting that they preferentially target different populations of 5-HT1A receptors. However, most previous studies used invasive and regionally-limited approaches. In this context, [18 F]FDG-PET imaging constitutes an interesting technique as it enables to non-invasively map the regional brain activity changes following a pharmacological challenge in conscious animals. We report here the evaluation of cerebral glucose metabolism following intraperitoneal injection of different doses of NLX-112 or NLX-101 in conscious or isoflurane-anesthetized rats. The biased agonists produced different metabolic "fingerprints" with distinct regional preferences, consistently with previous studies. At equal doses, the effect of NLX-101 was less marked than NLX-112 in the piriform cortex, the striatum (in terms of inhibition), and in the pontine nuclei and the cerebellum (in terms of activation); furthermore, only NLX-112 increased the glucose metabolism in the parietal cortex, whereas only NLX-101 induced a clear activation in the colliculi and the frontal cortex, which may be related to its distinctive pro-cognitive profile. Both agonists effects were almost completely unapparent in anesthetized animals, underlining the importance of studying serotonergic neurotransmission in conscious state. In this regard, [18 F]FDG-PET imaging seems very complementary with other functional imaging techniques such as pharmacological MRI.

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