Brain regions associated with inverse incentive learning: c-Fos immunohistochemistry after haloperidol sensitization on the bar test in rats

•We pair low-dose of haloperidol with the environment of a bar test.•Pairing daily haloperidol with the bar test produces sensitized descent latencies.•Unpaired rats received haloperidol in their home cages; they did not sensitize.•Paired rats have less c-Fos in the nucleus accumbens core and ventral pallidum.•Paired and unpaired have less c-Fos in the striatum and nucleus accumbens shell. Inverse incentive learning is the loss by stimuli of their ability to elicit approach and other responses. We used c-Fos immunohistochemistry to identify brain regions associated with inverse incentive learning. Rats that had daily treatments with haloperidol (0.25mg/kg) paired with placing their forepaws on a horizontal bar elevated 10cm above the floor initially descended almost immediately but over days descent latencies grew longer, revealing inverse incentive learning. Control rats that were tested daily and received haloperidol (Unpaired group) or saline later in their home cage showed no evidence of increased descent latencies. On the final test day, all groups were tested after haloperidol and only the Paired group showed increased descent latencies. c-Fos levels in the nucleus accumbens core and ventral pallidum were lower in the Paired group than in the Unpaired and Saline groups even though all groups received haloperidol on the test day. Compared to the Saline group both the Paired and Unpaired groups showed evidence of lower c-Fos levels in the dorsal striatum and nucleus accumbens shell, possibly a result of daily haloperidol injections. No group differences in c-Fos were found in the piriform cortex, ventral hippocampus, ventral tegmental area or lateral habenula. Results reveal, by means of different patterns of c-Fos expression, brain region-specific changes in neuronal activity associated with inverse incentive learning. Results support possible underlying neuroplastic changes for learned decreases in responsivity to environmental stimuli.