Updated overview of the putative role of the serotoninergic system in obsessive-compulsive disorder

Abstract

The pathophysiology of obsessive-compulsive disorder (OCD) remains unknown. However, increasing attention has been paid to the putative role of the serotoninergic system, the strongest evidence being based on the widely demonstrated efficacy of serotonin (5HT) reuptake inhibitor antidepressants in the treatment of OCD. The therapeutic effects are correlated with changes in peripheral parameters of 5HT function, which have been found to be altered in OCD, suggesting the possibility of reduced 5HT reuptake capacity. This could reflect a compensatory mechanism presumably due to decreased availability of extracellular 5HT, as evidenced by data derived from direct assessment of central 5HT neurotransmission. The development of new neurochemical probes that explore the sensitivity of various 5HT receptor subtypes has provided precious information. m-Chlorophenylpyperazine (m-CPP), an agonist to 5HT1A, 5HT1D, and 5HT2C receptors, and which also blocks 5HT3 receptors, exacerbates OC symptoms. In contrast, neither MK-212 (6-chloro-2-[1-piperazinyl]-pyrazine), a 5HT1A and 5HT2C receptor agonist, nor ipsapirone or buspirone, which acts as an agonist to 5HT1A receptors, have any effect on OC symptom severity. This suggests the potential implication of the 5HT1D receptor, as shown by the aggravation of OC manifestations in response to sumatriptan, a selective 5HT1D receptor agonist. The 5HT3 plays no specific role, given the lack of influence of the 5HT3 antagonist ondansetron, on OC symptom intensity. Further studies are required to elucidate the pharmacological molecular determinants of the putative 5HT1D receptor dysfunction.

Keywords: 5HT1D receptor agonists; obsessive-compulsive disorder; receptors; serotonin; serotonin reuptake inhibitors.

Figure 1

Schematic representation of the serotoninergic projections from the brainstem raphe nuclei to the forebrain and relationship with the cortico-subcortical loops. The cell bodies of the serotoninergic neurons are present in the brainstem raphe nuclei. They provide important innervations to a wide range of limbic target regions in the forebrain, comprising the orbital prefrontal and anterior cingulate cortices, ventral striatum, and thalamus belonging to the orbitofrontal and anterior cingulate loops, and other related structures, especially the amygdala, hippocampus, and hypothalamus.