Unveiling the role of melatonin MT2 receptors in sleep, anxiety and other neuropsychiatric diseases: a novel target in psychopharmacology

Abstract

Background: Melatonin (MLT) is a pleiotropic neurohormone controlling many physiological processes and whose dysfunction may contribute to several different diseases, such as neurodegenerative diseases, circadian and mood disorders, insomnia, type 2 diabetes and pain. Melatonin is synthesized by the pineal gland during the night and acts through 2 G-protein coupled receptors (GPCRs), MT1 (MEL1a) and MT2 (MEL1b). Although a bulk of research has examined the physiopathological effects of MLT, few studies have investigated the selective role played by MT1 and MT2 receptors. Here we have reviewed current knowledge about the implications of MT2 receptors in brain functions.

Methods: We searched PubMed, Web of Science, Scopus, Google Scholar and articles' reference lists for studies on MT2 receptor ligands in sleep, anxiety, neuropsychiatric diseases and psychopharmacology, including genetic studies on the MTNR1B gene, which encodes the melatonin MT2 receptor.

Results: These studies demonstrate that MT2 receptors are involved in the pathophysiology and pharmacology of sleep disorders, anxiety, depression, Alzheimer disease and pain and that selective MT2 receptor agonists show hypnotic and anxiolytic properties.

Limitations: Studies examining the role of MT2 receptors in psychopharmacology are still limited.

Conclusion: The development of novel selective MT2 receptor ligands, together with further preclinical in vivo studies, may clarify the role of this receptor in brain function and psychopharmacology. The superfamily of GPCRs has proven to be among the most successful drug targets and, consequently, MT2 receptors have great potential for pioneer drug discovery in the treatment of mental diseases for which limited therapeutic targets are currently available.

Fig. 1

MT₂ receptor ligands used in psychopharmacological studies. Binding affinity constants have been assessed on the recombinant human MT₁ and MT₂ receptors expressed in NIH3T3 cells for melatonin, UCM765, IIK7 and K185 and in COS-7 cells for 4-phenyl-2-propionamidotetralin (4P-PDOT).

Fig. 2

The MT₂ receptor partial agonist UCM765 promotes non–rapid eye movement sleep (NREMS; modified from Ochoa-Sanchez and colleagues, with permission). (Top right) Schematic depiction of a rat with electrodes implanted for electroencephalography (EEG) and electromyography (EMG) recordings. (Top left) Example of an EEG/EMG recording highlighting a period of wakefulness, NREMS and rapid-eye movement sleep (REMS). (Bottom) The effect of UCM765 (40 mg/kg, subcutaneous) on NREMS latency, NREMS time, REMS time, wakefulness time and number of sleep spindles during the light and dark phases of the 12:12 hour light–dark cycle. **p < 0.01 and ***p < 0.001 versus vehicle, 2-way mixed-design analysis of variance plus Newman–Keuls test for post hoc comparison.

Fig. 3

The MT₂ receptor partial agonist UCM765 increases the neural activity of the reticular thalamus, enhancing the rhythmic burst activity (modified from Ochoa-Sanchez and colleagues, with permission). (Right) A rat under anesthesia and restrained in a stereotaxic apparatus. An electrode is lowered into the reticular thalamus according to the Paxinos and Watson atlas.(Left) Reticular thalamic neurons bear MT₂ receptors. (Top) An injection of UCM765 (20 mg/kg, intravenous) increases the firing activity of a reticular thalamic neuron.