5-HT(2C) receptors are predominantly localised in the brain and their dysregulation may contribute to particular symptoms of anxiety and depression. The marked affinity of several clinically established psychotropic agents sites (e.g.,
tricyclic antidepressants,
clozapine,
fluoxetine) for
5-HT(2C) receptor has generated interest in the therapeutic potential of selective, high affinity
5-HT(2C) receptor ligands. Like the selective
serotonin re-uptake inhibitor (SSRI)
fluoxetine, high affinity selective agonists such as
Ro 60-0175 and Ro 60-0332 have potent in vivo activity in animal models suggestive of therapeutic action against depression,
obsessive-compulsive disorder (OCD) and
panic disorders. In contrast,
5-HT(2C) receptor antagonists such as
SB-200646A or
SB-221284 show signs of
anxiolytic-like activity in tests for conditioned and phobic-like anxiety in rodents whereas they are inactive in tests indicative of
antidepressant, antiOCD and antipanic activity. These results are consistent with an important hypothesis proposing that
5-HT has a complex, dual action on the neural mechanism of anxiety by either facilitating or inhibiting different kinds of anxiety in different brain regions. They also suggest that
5-HT(2C) receptor subtypes play an important role in the therapeutic properties of
SSRIs. Certain
5-HT(2C) receptor antagonists may possess negative efficacy at 5-HT(2C) receptors and, as inverse agonists, may control constitutive receptor activity possibly characterising some psychopathological states. Receptor variants exist in the human population and indicate possible associations between somatic mutations in the
5-HT(2C) receptor and psychopathology or response to
drug treatment. Selective
5-HT(2C) receptor ligands may offer innovative and improved therapeutic opportunities for the
biological treatment of specific aspects of psychiatric syndromes.