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

Abstract

Perseverative behavior has been highly implicated in addiction. Activation of serotonin 2C receptors (5-HTRs) attenuates cocaine and high caloric food intake, but whether a 5-HTR agonist can reduce high caloric diet (HCD) or methamphetamine (METH) intake and response perseveration remains unknown. Clarifying the role of 5-HTRs 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-HTR 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-HTR 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-HTR 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-HTR for these behavioral effects.

Prader–Willi syndrome imprinting centre deletion mice have impaired baseline and 5-HT2CR-mediated response inhibition

“…Moreover, this apparent opposite effect of WAY163909 administration, decreasing impulsivity in the SSRTT and increasing feeding, may be a result of effects of 5-HT 2C R agonism in different parts of the brain with distinct dissociable functions on behaviour. However, a recent study (35) has demonstrated that agonism of the 5-HT 2C R with WAY163909, affected response control, akin to the improved stopping we have found here, in combination with consumption of a high calorific diet suggesting a relationship between dietary habits and decision-making strategies with 5-HT 2C R at the nexus (36,37).…”

Impaired cognitive behavioral flexibility following methamphetamine or high caloric diet consumption: a common 5-HT2C mechanism?

“…These brain regions comprise the mesolimbic dopamine reward pathway that has been implicated in substance abuse, overeating of high caloric foods, and perseverative impairments during discrimination reversal learning procedures [3,7]. Perez Diaz et al [4] extend these previous findings by suggesting that 5-HT 2C activation attenuates methamphetamine-related and high caloric dietrelated increases in perseverative responding in a discrimination reversal learning procedure.…”

“…Although the findings from Perez Diaz et al [4] are provocative, the results prompt several questions like any good experiment does. Three will be mentioned.…”

“…Overall, Perez Diaz et al [4] provide compelling preclinical evidence that 5-HT 2C activation decreases perseverative behavior regardless of experimental drug or diet history. The use of nonhuman primates as research subjects in the Perez Diaz et al [4] enhances the potential translatability of these findings to positive clinical outcomes [8]. The current opioid and obesity public health crises has reinvigorated preclinical and clinical research efforts to develop safer and more effective treatment.…”

“…In their recent Neuropsychopharmacology article, Perez Diaz et al [4] propose a novel G protein-coupled receptor target to attenuate increased perseverative behavior in a discrimination reversal learning procedure following long-term methamphetamine selfadministration or high caloric diet consumption in nonhuman primates. Perez Diaz et al [4] initially trained female rhesus monkeys to respond for a food reinforcer (M&Ms, Skittles) during a discrimination reversal learning procedure. Once trained, the subjects underwent a reversal trial where the food reinforcer was hidden under one of the previously unreinforced objects.…”