The Serotonin-7 Receptor as a Novel Therapeutic Target

The Serotonin-7 Receptor as a Novel Therapeutic Target

Stephen M. Stahl, MD, PhD

Issue: Blockade of 5-HT7 receptors may be a novel therapeutic approach for achieving antidepressant and memory-enhancing actions.

There are more than a dozen receptor subtypes for serotonin (5-hydroxytryptamine, 5-HT), but only 2 of them are generally well known to clinical psychopharmacologists1: the 5-HT1A receptor, stimulation of which is linked to antidepressant and anxiolytic actions, and the 5-HT2A receptor, blockade of which is linked to the reduction of extrapyramidal side effects and other side effects of the second-generation atypical antipsychotics.1,2 Now comes the 5-HT7 receptor onto the scene,2-17 not just because of the development of specific compounds allowing characterization of this receptor,3,5,7-9 but also because of the discovery that several of the known antidepressants and antipsychotics block 5-HT7 receptors, and that this 5-HT7 antagonism may account in part for the therapeutic properties of these drugs, especially antidepressant actions.10-17

Localization and Function of 5-HT7 Receptors

Serotonin-7 receptors are postsynaptic G protein-linked receptors that may regulate serotonin-glutamate interactions.3,4,7 They are distributed in areas that explain their functions, namely, the suprachiasmatic nucleus of the hypothalamus; the hippocampus, cortex, and thalamus; and also in the midbrain raphe nuclei, probably on GABA interneurons or on glutamate terminals.3,4,7 Numerous animal studies have demonstrated the role of 5-HT7 receptors in preclinical antidepressant actions, learning, memory, sleep, and circadian rhythms.3-9

5-HT7 Receptors as Novel Therapeutic Targets

Although no selective 5-HT7 compounds are available for clinical use, numerous compounds are sufficiently potent blockers of 5-HT7 receptors such that 5-HT7 antagonism could theoretically contribute to their pharmacologic actions (Table 1).10-17 In particular, several of the compounds listed in Table 1 are effective antidepressants, and in animal models, the antidepressant efficacy of aripiprazole is reversed in animals lacking 5-HT7 receptors,8 and the serotonin release and antidepressant actions of selective serotonin reuptake inhibitors (SSRIs) are enhanced by selective 5-HT7 antagonists.3,5,8

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Three novel agents characterized as antipsychotics have 5-HT7 antagonist properties among their most potent pharmacologic actions (Figure 1),2,10,13,14 and 1 of these, lurasidone, in late-stage clinical development as an antipsychotic, is actually "5-HT7 preferring," with 5-HT7 antagonism its most potent property.13 Of these, amisulpride (not available in the United States) is a proven antidepressant.1,2,14 Theoretically, because of their even greater potency for 5-HT7 antagonism, lurasidone and asenapine are good candidates for clinical testing as antidepressants as well.

Combining agents such as lurasidone or asenapine with SSRIs would be predicted to enhance 5-HT release as well as to have antidepressant properties.3-5,8 Given the recent positive results as an antidepressant for the melatonergic/serotonergic agent agomelatine, which resets circadian rhythms,18 combining novel 5-HT7 antagonists with melatonin agonism may also enhance the antidepressant actions of 5-HT7 antagonists. In addition, preclinical studies3,5,8,9 suggest the possibility that agents with potent 5-HT7 antagonism may improve cognition, so cognition in depression, schizophrenia, and other illnesses is a theoretically attractive clinical target, for 5-HT7 antagonists as well.

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References

1. Stahl SM. Stahl’s Essential Psychopharmacology. 3rd ed. New York, NY: Cambridge University Press; 2008.

2. Stahl SM. Stahl’s Illustrated Antipsychotics. 2nd ed. New York, NY: Cambridge University Press; 2010.

3. Hedlund PB. The 5-HT7 receptor and disorders of the nervous system: an overview. Psychopharmacology (Berl). 2009;206(3):345-354. PubMed doi:10.1007/s00213-009-1626-0

4. Harsing LG Jr, Prauda I, Barkoczy J, et al. A 5-HT7 heteroreceptor-mediated inhibition of [3H]serotonin release in raphe nuclei slices of the rat: evidence for a serotonergic-glutamatergic interaction. Neurochem Res. 2004;29(8):1487-1497. PubMed doi:10.1023/B:NERE.0000029560.14262.39

5. Bonaventure P, Kelly L, Aluisio L, et al. Selective blockade of 5-hydroxytryptamine (5-HT)7 receptors enhances 5-HT transmission, antidepressant-like behavior, and rapid eye movement sleep suppression induced by citalopram in rodents. J Pharmacol Exp Ther. 2007;321(2):690-698. PubMed doi:10.1124/jpet.107.119404

6. Cuesta M, Clesse D, Pévet P, et al. New light on the serotonergic paradox in the rat circadian system. J Neurochem. 2009;110(1):231-243. PubMed doi:10.1111/j.1471-4159.2009.06128.x

7. Hedlund PB, Sutcliffe JG. Functional, molecular and pharmacological advances in 5-HT7 receptor research. Trends Pharmacol Sci. 2004;25(9):481-486. PubMed doi:10.1016/j.tips.2004.07.002

8. Sarkisyan G, Roberts AJ, Hedlund PB. The 5-HT7 receptor as a mediator and modulator of antidepressant-like behavior. Behav Brain Res. 2010;209(1):99-108. PubMed doi:10.1016/j.bbr.2010.01.022

9. Sarkisyan G, Hedlund PB. The 5-HT7 receptor is involved in allocentric spatial memory information processing. Behav Brain Res. 2009;202(1):26-31. PubMed doi:10.1016/j.bbr.2009.03.011

10. Monsma FJ Jr, Shen Y, Ward RP, et al. Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs. Mol Pharmacol. 1993;43(3):320-327. PubMed

11. Mullins UL, Gianutsos G, Eison AS. Effects of antidepressants on 5-HT7 receptor regulation in the rat hypothalamus. Neuropsychopharmacology. 1999;21(3):352-367. PubMed doi:10.1016/S0893-133X(99)00041-X

12. Roth BL, Craigo SC, Choudhary MS, et al. Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-6 and 5-hydroxytryptamine-7 receptors. J Pharmacol Exp Ther. 1994;268(3):1403-1410. PubMed

13. Shapiro DA, Renock S, Arrington E, et al. Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology. 2003;28(8):1400-1411. PubMed doi:10.1038/sj.npp.1300203

14. Lawler CP, Prioleau C, Lewis MM, et al. Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes. Neuropsychopharmacology. 1999;20(6):612-627. PubMed doi:10.1016/S0893-133X(98)00099-2

15. Ishibashi T, Horisawa T, Tokuda K, et al. Pharmacological profile of lurasidone, a novel antipsychotic agent with potent 5-hydroxytryptamine 7 (5-HT7) and 5-HT1A receptor activity. J Pharmacol Exp Ther. 2010;334(1):171-181. PubMed doi:10.1124/jpet.110.167346

16. Abbas AI, Hedlund PB, Huang X-P, et al. Amisulpride is a potent 5-HT7 antagonist: relevance for antidepressant actions in vivo. Psychopharmacology (Berl). 2009;205(1):119-128. PubMed doi:10.1007/s00213-009-1521-8

17. Smith C, Rahman T, Toohey N, et al. Risperidone irreversibly binds to and inactivates the h5-HT7 serotonin receptor. Mol Pharmacol. 2006;70(4):1264-1270. PubMed doi:10.1124/mol.106.024612

18. Stahl SM, Fava M, Trivedi MH, et al. Agomelatine in the treatment of major depressive disorder: an 8-week, multicenter, randomized, placebo-controlled trial. J Clin Psychiatry. 2010;71(5):616-626. PubMed doi:10.4088/JCP.09m05471blu

Brainstorms is a section of The Journal of Clinical Psychiatry aimed at providing updates of novel concepts emerging from the neurosciences that have relevance to the practicing psychiatrist.

From the Neuroscience Education Institute in Carlsbad, California, and the Department of Psychiatry at the University of California San Diego, and the Department of Psychiatry at the University of Cambridge, Cambridge, United Kingdom.

For reprint and financial disclosure information, go to www.psychiatrist.com/brainstorms.

doi:10.4088/JCP.10bs06601gry

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