WAY-208466, a 5-HT₆ receptor agonist, increases food motivation in primates: A behavioural and PET imaging study...

The 5-HT₆ receptor (5-HT6R) is highly expressed in the anterior striatum, a region involved in food-intake and anxiety-related behaviours that shows abnormal activity in anorexia nervosa (AN) patients. Indeed, 5-HT6R antagonists decrease food motivation across species. Rodent studies have shown the acute anxiolytic properties of WAY-208466, a selective 5-HT6R agonist. Thus, we hypothesized that this agent could increase food motivation and decrease anxiety-related behaviours by impacting cortico-striatal circuits. We administered acute (0.1 mg/kg) and subchronic (0.03 and 0.1 mg/kg) intramuscular injections to four macaques performing a food-choice task and expressing spontaneous behaviours. We used PET imaging with the [¹⁸F]2FNQ1P specific tracer to determine 5-HT6R occupancy in several regions that could be linked with the induced behavioural changes. Acute and subchronic activation of 5-HT6R transmission led to a reversible increase in food motivation. WAY-208466 also decreased anxiety-like behaviours when given acutely but not subchronically. However, in the subchronic protocol, the higher dose led to increased activity characterized by movements and object-related behaviour expression. PET imaging revealed that these behavioural changes could be sustained by cortico-striatal circuits involved in food intake. These findings demonstrate that this 5-HT6R agonist subchronic treatment successfully increases food motivation but does not fully achieve the expected anxiolytic effect in monkeys. It suggests that targeting 5-HT6Rs may be a promising approach for treating the restrictive subtype of AN, which, unlike anxiety, has not been shown to benefit from treatment with selective serotonin reuptake inhibitors.