5-HT2A and 5-HT2C receptor antagonists have opposing effects on a measure of impulsivity:: interactions with global 5-HT depletion

Rationale: Global serotonin (5-HT) depletion increases the number of premature responses made on the five-choice serial reaction time task (5CSRT) in rats. In contrast, the 5-HT2A receptor antagonist M100907 decreases this measure of impulsivity. Mounting evidence suggests that 5-HT2A and 5-HT2C receptors have opposing effects on behaviour, and that the 5-HT2C receptor antagonist SB 242084 produces a pattern of behaviour similar to 5-HT depletion. Objectives: To assess the effects of 5-HT2A and 5-HT2C receptor antagonists on performance of the 5CSRT, to directly compare the effects of these drugs with those of ICV 5,7-dihydroxytryptamine (5,7-DHT) lesions and to investigate whether 5-HT depletion affects the action of these agents. Methods: The effects of M100907 (0, 0.01, 0.03, 0.1 mg/kg IP) and SB 242084 (0, 0.1, 0.25, 0.5 mg/kg IP) were investigated on performance of the 5CSRT in both ICV 5,7-DHT-lesioned and sham-operated rats. Results: ICV 5,7-DHT lesions, which significantly decreased forebrain levels of 5-HT by around 90%, increased levels of premature responding, decreased omissions and the latency to respond correctly, yet did not affect performance accuracy. M100907 decreased premature responding in sham-operated controls but not in 5-HT-depleted rats. In contrast, SB 242084 increased premature responding in all animals, and also decreased the latency to make a correct response in sham-operated controls. Conclusions: These data support the view that serotonergic regulation of impulsive behaviour through different members of the 5-HT2 receptor family is functionally heterogeneous. Although both 5-HT2A and 5-HT2C receptors participate in controlling this form of impulsive action, their relative contribution may depend on the endogenous state of the 5-HT system.