The role of 5-HT_2A and 5-HT_2C receptors in the signal attenuation rat model of obsessive-compulsive disorder

Serotonin 5-HT_2A and 5-HT_2C receptors have been implicated in the pathophysiology of obsessive-compulsive disorder (OCD) and in the mechanism mediating the anti-compulsive effects of serotonin reuptake inhibitors. Yet it is currently unclear whether activation or blockade of these receptors would have an anti-compulsive effect. The present study tested the effects of 5-HT_2A and 5-HT_2C activation and blockade in the signal attenuation rat model of OCD. In this model, 'compulsive' behaviour is induced by attenuating a signal indicating that a lever-press response was effective in producing food. Experiments 1-4 revealed that systemic administration of the 5-HT_2C antagonist RS 102221 (2 mg/kg) selectively decreases compulsive lever-pressing, whereas systemic administration of the 5-HT_2A antagonist MDL 11,939 (0.2-5 mg/kg) or of the 5-HT_2A/2C agonist DOI (0.05-5 mg/kg) did not have a selective effect on this behaviour. Experiments 5 and 6 found that systemic co-administration of DOI (0.5 mg/kg) with MDL 11,939 (1 mg/kg) or with RS 102221 (2 mg/kg) had a non-selective effect on lever-press responding, with the former manipulation increasing and the latter manipulation decreasing lever-pressing. Finally, experiment 7 demonstrated that administration of RS 102221 directly into the orbitofrontal cortex also exerts an anti-compulsive effect. The results of these experiments suggest that blockade of 5-HT_2C receptors may have an anti-compulsive effect in OCD patients, and that this effect may be mediated by 5-HT_2C receptors within the orbitofrontal cortex.