Sunday, 21 July 2013

The 5-HT2C receptor

Interestingly one of the subtype of receptors that the neurotransmitter serotonin binds to and activates, the 5-HT2C receptor (which was once called the 5-HT1C receptor), is found on the X chromosome.1 What this means is that males have one copy of the gene encoding the 5-HT2C receptor, whereas women have two copies of this gene. Practically this means that if there is a defect in the gene that causes less of the 5-HT2C receptor protein (as you may or may not know all receptors are, in fact, proteins) to be synthesised and a man inherits it, he'll suffer more than a women that inherits one copy of the defective gene and one functional 5-HT2C receptor gene on their other X chromosome.

The role of the 5-HT2C receptor is complex. To the cell on which 5-HT2C receptors are expressed they are excitatory – that is, they increase the activity of the cells on which they are expressed. But because there are neurons (the electrically signalling cells of the brain, spinal cord and nerves) that, when excited, release inhibitory neurotransmitters like GABA, 5-HT2C receptors can, in some brain regions, have indirect (i.e. via these inhibitory GABAergic interneurons as they're called) inhibitory functions, that is they can reduce cellular activity in these regions.2

It appears to, via this indirect mechanism, to suppress the release of dopamine and norepinephrine in certain parts of the brain, particularly in the mesolimbic pathway.2-4 Which is a part of the brain from which the rewarding (or pleasurable) effects of recreational drugs, certain behaviours (like gambling) and even food originates from. It has hence been found that 5-HT2C antagonists (or blockers) facilitate the release of dopamine in the mesolimbic pathway induced by drugs of abuse like nicotine, cocaine, morphine and phencyclidine (PCP), hence potentially amplifying their rewarding or pleasurable effects. This is kind of ironic when you think about how patients with schizophrenia have a far higher incidence of substance abuse problems, including tobacco smoking addiction, seeing how many of the newer antipsychotics on the market that are frequently used to treat patients schizophrenia do, in fact, antagonise the 5-HT2C receptor. Albeit they also antagonise a few of the dopamine receptors that are involved in the pleasurable effects of these drugs but seeing how this effect is usually weaker than their inhibitory effects on the 5-HT2C receptor you could make the argument that they likely overall cause an increased liability to amplifying the addictive potential of recreational drugs.5,6

It has also been discovered that 5-HT2C receptors regulate feeding – 5-HT2C antagonists are known to cause an increase in appetite in humans and this can lead to obesity, as is exemplified by the fact that several of the newer antipsychotics like clozapine and olanzapine that antagonise the 5-HT2C receptors lead frequently to weight gain and obesity. Conversely 5-HT2C agonists are known to suppress appetite and the drug lorcaserin was recently approved by the US FDA for the treatment of obesity.

5-HT2C receptors also regulate mood and perception. For instance, the 5-HT2C agonist vabicaserin was being developed as a treatment for schizophrenia, until development was ceased in 2010 for a reason that escapes me. 5-HT2C antagonists display antidepressant activity, with several commercially (or clinically) available antidepressants such as fluoxetine (PROZAC), agomelatine (VALDOXAN), mirtazapine (AVANZA, REMERON), amitriptyline (ELAVIL, ENDEP) and mianserin (LUMIN, TOLVON) displaying clinically-significant affinity towards the receptor as an antagonist.7 It is possible that it is, in part, by antagonising the 5-HT2C receptor that atypical (newer) antipsychotics like olanzapine and aripiprazole that they manage to speed up and improve response rates to antidepressant therapy.7-10

Reference List:

  1. Milatovich A, Hsieh C-L, Bonaminio G, Tecott L, Francke U. Serotonin receptor 1c gene assigned to X chromosome in human (band q24) and mouse (bands D-F4). Hum Mol Genet [Internet]. 1992 Dec 1 [cited 2013 Jul 22];1(9):681–4. Available from:
  2. Invernizzi RW, Pierucci M, Calcagno E, Di Giovanni G, Di Matteo V, Benigno A, et al. Selective activation of 5-HT2C receptors stimulates GABA-ergic function in the rat substantia nigra pars reticulata: A combined in vivo electrophysiological and neurochemical study. Neuroscience [Internet]. 2007 Feb 23 [cited 2013 Jul 22];144(4):1523–35. Available from:
  3. Millan M, Dekeyne A, Gobert A. Serotonin (5-HT)2C receptors tonically inhibit dopamine (DA) and noradrenaline (NA), but not 5-HT, release in the frontal cortex in vivo. Neuropharmacology [Internet]. 1998 Jul [cited 2013 Jul 22];37(7):953–5. Available from:
  4. Di Giovanni G, De Deurwaerdére P, Di Mascio M, Di Matteo V, Esposito E, Spampinato U. Selective blockade of serotonin-2C/2B receptors enhances mesolimbic and mesostriatal dopaminergic function: a combined in vivo electrophysiological and microdialysis study. Neuroscience [Internet]. 1999 Jun [cited 2013 Jul 22];91(2):587–97. Available from:
  5. Porras G, Matteo VD, Fracasso C, Lucas G, Deurwaerdère PD, Caccia S, et al. 5-HT2A and 5-HT2C/2B Receptor Subtypes Modulate Dopamine Release Induced in Vivo by Amphetamine and Morphine in Both the Rat Nucleus Accumbens and Striatum. , Published online: 18 July 2001; | doi:101016/S0893-133X(01)00333-5 [Internet]. 2001 Jul 18 [cited 2013 Jul 22];26(3):311–24. Available from:
  6. Navailles S, De Deurwaerdère P, Porras G, Spampinato U. In Vivo Evidence that 5-HT2C Receptor Antagonist but not Agonist Modulates Cocaine-Induced Dopamine Outflow in the Rat Nucleus Accumbens and Striatum. Neuropsychopharmacology [Internet]. 2003 Oct 15 [cited 2013 Jul 22];29(2):319–26. Available from:
  7. Jenck F, Moreau J-L, Mutel V, Martin JR, Haefely WE. Evidence for a role of 5-HT1C receptors in the antiserotonergic properties of some antidepressant drugs. European Journal of Pharmacology [Internet]. 1993 Feb 9 [cited 2013 Jul 22];231(2):223–9. Available from:
  8. Dolder CR, Nelson M, Snider M. Agomelatine Treatment of Major Depressive Disorder. Annals of Pharmacotherapy. 2008 Nov 18;42(12):1822–31.
  9. Jenck F, Moreau J-L, Mutel V, Martin JR. Brain 5-HT1C receptors and antidepressants. Progress in Neuro-Psychopharmacology and Biological Psychiatry [Internet]. 1994 May [cited 2013 Jul 22];18(3):563–74. Available from:
  10. Jenck F, Bös M, Wichmann J, Stadler H, Martin J, Moreau J. The role of 5ht2c receptors in affective disorders. Expert Opinion on Investigational Drugs [Internet]. 1998 Oct [cited 2013 Jul 22];7(10):1587–99. Available from:

No comments:

Post a Comment