Central administration of ghrelin induces conditioned avoidance in rodents

Feelings of hunger carry a negative-valence (emotion) signal that appears to be conveyed through agouti-related peptide (AgRP) neurons in the hypothalamic arcuate nucleus. The circulating hunger hormone, ghrelin, activates these neurons although it remains unclear whether it also carries a negative-valence signal. Given that ghrelin also activates pathways in the midbrain that are important for reward, it remains possible that ghrelin could act as a positive reinforcer and hence, carry a positive-valence signal. Here we used condition preference/avoidance tests to explore the reinforcing/aversive properties of ghrelin, delivered by intracerebroventricular (ICV) injection (2 µg/injection once a day for 4 days). We found that ICV ghrelin produces conditioned avoidance, both in a conditioned place preference/avoidance test (CPP/CPA, in which the animals avoid a chamber previously paired to ghrelin injection) and in a conditioned flavor preference/avoidance test (CFP/CFA, in which the animals consume/avoid a taste previously paired to ghrelin injection). These effects of ghrelin to induce a CPA were observed when conditioning to ghrelin occurred in the absence or presence of food. We did not find evidence, however, that brain ghrelin delivery to rats induces malaise (in the pica test). Our data indicate that ICV ghrelin carries a negative-valence signal consistent with its role as a circulating hunger hormone and with its effects to activate AgRP neurones.