New therapeutic opportunities for 5-HT2C receptor ligands in neuropsychiatric disorders

Pharmacol Ther. 2016 Jan;157:125-62. doi: 10.1016/j.pharmthera.2015.11.009. Epub 2015 Nov 23.

Abstract

The 5-HT2C receptor (R) displays a widespread distribution in the CNS and is involved in the action of 5-HT in all brain areas. Knowledge of its functional role in the CNS pathophysiology has been impaired for many years due to the lack of drugs capable of discriminating among 5-HT2R subtypes, and to a lesser extent to the 5-HT1B, 5-HT5, 5-HT6 and 5-HT7Rs. The situation has changed since the mid-90s due to the increased availability of new and selective synthesized compounds, the creation of 5-HT2C knock out mice, and the progress made in molecular biology. Many pharmacological classes of drugs including antipsychotics, antidepressants and anxiolytics display affinities toward 5-HT2CRs and new 5-HT2C ligands have been developed for various neuropsychiatric disorders. The 5-HT2CR is presumed to mediate tonic/constitutive and phasic controls on the activity of different central neurobiological networks. Preclinical data illustrate this complexity to a point that pharmaceutical companies developed either agonists or antagonists for the same disease. In order to better comprehend this complexity, this review will briefly describe the molecular pharmacology of 5-HT2CRs, as well as their cellular impacts in general, before addressing its central distribution in the mammalian brain. Thereafter, we review the preclinical efficacy of 5-HT2C ligands in numerous behavioral tests modeling human diseases, highlighting the multiple and competing actions of the 5-HT2CRs in neurobiological networks and monoaminergic systems. Notably, we will focus this evidence in the context of the physiopathology of psychiatric and neurological disorders including Parkinson's disease, levodopa-induced dyskinesia, and epilepsy.

Keywords: 5-HT receptors; Dopamine; G protein coupled receptors; GABA; Receptor oligomers; mRNA editing.

Publication types

  • Review

MeSH terms

  • Animals
  • Central Nervous System / metabolism
  • Central Nervous System Diseases / drug therapy
  • Central Nervous System Diseases / metabolism*
  • Humans
  • Ligands
  • Neurotransmitter Agents / metabolism
  • Receptor, Serotonin, 5-HT2C / metabolism*
  • Schizophrenia / drug therapy
  • Schizophrenia / metabolism*

Substances

  • Ligands
  • Neurotransmitter Agents
  • Receptor, Serotonin, 5-HT2C