SB-258585 reduces food motivation while blocking 5-HT₆ receptors in the non-human primate striatum

The interest in new 5-HT₆ agents stems from their ability to modulate cognition processing, food motivation and anxiety-like behaviors. While these findings come primarily from rodent studies, no studies on primates have been published. Furthermore, our understanding of where and how they act in the brain remains limited. Although the striatum is involved in all of these processes and expresses the highest levels of 5-HT₆ receptors, few studies have focused on it. We thus hypothesized that 5-HT₆ receptor blockade would influence food motivation and modulate behavioral expression in non-human primates through striatal 5-HT₆ receptors. This study thus aimed to determine the effects of acute administration of the SB-258585 selective 5-HT₆ receptor antagonist on the feeding motivation and behaviors of six male macaques. Additionally, we investigated potential 5-HT₆ targets using PET imaging to measure 5-HT₆ receptor occupancy throughout the brain and striatal subregions. We used a food-choice task paired with spontaneous behavioral observations, checking 5-HT₆ receptor occupancy with the specific PET imaging [¹⁸F]2FNQ1P radioligand. We demonstrated, for the first time in non-human primates, that modulation of 5-HT₆ transmission, most likely through the striatum (the putamen and caudate nucleus), significantly reduces food motivation while exhibiting variable, weaker effects on behavior. While these results are consistent with the literature showing a decrease in food intake in rodents and proposing that 5-HT₆ receptor antagonists can be used in obesity treatment, they question the antagonists' anxiolytic potential.