Genetic and pharmacological evidence that 5-HT2C receptor activation, but not inhibition, affects motivation to feed under a progressive ratio schedule of reinforcement

Previous work showed that 5-HT_2C receptor agonists reduce cocaine self-administration on a progressive ratio (PR) schedule of reinforcement, whereas a 5-HT_2C receptor antagonist enhances responding for cocaine. The present experiments examined the effects of Ro60-0175 (5-HT_2C agonist) and SB242084 (5-HT_2C receptor antagonist) in rats on responding for food on a PR schedule; responding was also determined in mice lacking functional 5-HT_2C receptors. In food-restricted rats, lever pressing reinforced by regular food pellets or sucrose pellets was reduced by Ro60-0175. This effect was blocked by SB242084, and was absent in mice lacking functional 5-HT_2C receptors. A number of studies examined the effects of SB242084 on responding for food under a variety of conditions. These included manipulation of food type (regular pellets versus sucrose pellets), nutritional status of the animals (food restriction versus no restriction), and rate of progression of the increase in ratio requirements on the PR schedule. In all cases there was no evidence of enhanced responding for food by SB242084. Mice lacking functional 5-HT_2C receptors did not differ from wildtype mice in responding for food in either food-restricted or non-restricted states. The effects of Ro60-0175 are consistent with its effects on food consumption and motivation to self-administer cocaine. Unlike their effects on cocaine self-administration, pharmacological blockade of 5-HT_2C receptors, and genetic disruption of 5-HT_2C receptor function do not alter the motivation to respond for food. Because the 5-HT_2C receptor exerts a modulatory effect on dopamine function, the differential effects of reduced 5-HT_2C receptor mediated transmission on responding for food versus cocaine may relate to a differential role of this neurotransmitter in mediating these two behaviours.