The role of 5-HT2C receptors in affective disorders.
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.
ROCHE Pharma Division, Preclinical CNS Research, CH 4070, Basel, Switzerland.
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F
Jenck
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M
Bös
J
J
Wichmann
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H
Stadler
J R
JR
Martin
J L
JL
Moreau