The opioid system contributes to the acquisition of reinforcement for dietary fat but is not required for its maintenance

• Naltrexone reduced fat intake in mice well habituated to fat ingestion.
• Naltrexone suppressed daily increases of fat intake in mice naïve to fat ingestion.
• Naltrexone did not affect reinforcement for fat in well-habituated mice.
• Naltrexone suppressed the acquisition of reinforcement for fat in naïve mice.

The opioid system plays an important role in ingestive behavior, especially with regard to palatable high-fat or sweetened foods. In the present study, we investigated the role of the opioid system in the regulation of ingestive behavior in mice with regard to dietary fat intake, reinforcement, and particularly the processes involved in development of these behavior types. Subcutaneous administration of the non-selective opioid receptor antagonist naltrexone (0.5 or 2.0 mg/kg body weight [BW]) reduced the spontaneous intake of fat emulsion (Intralipid). We investigated the effect of naltrexone on reinforcement by using an operant behavioral paradigm under a progressive ratio schedule in which the number of lever presses required to obtain a test sample increased progressively. Mice showed stronger reinforcement by Intralipid as a function of concentration. However, naltrexone (0.5 or 2.0 mg/kg BW) did not affect reinforcement at any concentration of Intralipid in mice that had repeatedly ingested Intralipid before testing was carried out. Intralipid ingestion also induced conditioned place preference (CPP), which is another evaluation index of reinforcement. High-dose naltrexone (2.0 mg/kg BW) administration during CPP conditioning suppressed the reinforcement induced by Intralipid ingestion, although the drug administration (0.5 or 2.0 mg/kg BW) during CPP testing did not affect reinforced behavior. These results suggest that the amount of fat ingestion and reinforcement for fat ingestion are separately regulated by the opioid system. Furthermore, our results indicate that the opioid system plays an important role in acquiring reinforcement for fat but is not required for maintenance of learned reinforcement.