Effects of long-term high-fat food or methamphetamine intake and serotonin 2C receptors on reversal learning in female rhesus macaques.

Perseverative behavior has been highly implicated in addiction. Activation of serotonin 2C receptors (5-HT2CRs) attenuates cocaine and high caloric food intake, but whether a 5-HT2CR agonist can reduce high caloric diet (HCD) or methamphetamine (METH) intake and response perseveration remains unknown. Clarifying the role of 5-HT2CRs in these behaviors will improve knowledge of neurochemical processes that regulate flexible decision-making and whether improvements in decision-making are accompanied by decreases in HCD or METH intake. This study evaluated the effects of long-term HCD and METH intake on reversal learning in female rhesus monkeys. The effects of the 5-HT2CR agonist WAY163909 on reversal learning before and after extended HCD or METH intake, and on food intake, was also tested. Moreover, we examined whether the 5-HT2CR is necessary for the effects of WAY163909. WAY163909 was given prior to reversal learning at baseline and after extended HCD or METH intake, and prior to measures of food intake. Extended intake of METH or the HCD increased perseverative errors during reversal. WAY163909 increased correct responses and decreased perseverative errors, both before and after extended HCD or METH intake. Similarly, WAY163909 decreased consumption of a HCD, but not a low caloric diet. The effects of WAY163909 on all these measures were blocked by co-administration with a 5-HT2CR antagonist. These data indicate that long-term HCD or METH intake disrupts flexible decision-making. Further, the results suggest that reductions in food intake produced by WAY163909 are associated with parallel improvements in decision-making strategies, underscoring the role of the 5-HT2CR for these behavioral effects.