SB-258585 reduces food motivation while blocking 5-HT 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-HT receptor blockade would influence food motivation and modulate behavioral expression in non-human primates through striatal 5-HT receptors. This study thus aimed to determine the effects of acute administration of the SB-258585 selective 5-HT receptor antagonist on the feeding motivation and behaviors of six male macaques. Additionally, we investigated potential 5-HT targets using PET imaging to measure 5-HT receptor occupancy throughout the brain and striatal subregions. We used a food-choice task paired with spontaneous behavioral observations, checking 5-HT receptor occupancy with the specific PET imaging [F]2FNQ1P radioligand. We demonstrated, for the first time in non-human primates, that modulation of 5-HT 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-HT receptor antagonists can be used in obesity treatment, they question the antagonists' anxiolytic potential.