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.