| Abstract No.: | B-E2167 |
| Country: | Canada |
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| Title: | SELECTIVE INCREASE OF SLOW WAVE SLEEP (SWS) BY MELATONIN 2 RECEPTORS |
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| Authors/Affiliations: | 4 Rafael Ochoa-Sánchez *; 2 Gilberto Spadoni ; 2 Annalida Bedini ; 5 Marco Mor; 5 Silvia Rivara ; 1 Franco Fraschini ; 2 Giorgio Tarzia; 3 Gabriella Gobbi;
1 Dept. of Pharmacology, Chemiotherapy and Medical Toxicology, Univ.of Milan, Italy; 2 Inst. of Pharmaceutical Chemistry and Toxicology, Univ of Urbino, Italy; 3 Neurobiological Psychiatry Unit, Dept. of Psychiatry, McGill University, Montreal, QC, Canada; Centre de Recherche Fernand-Seguin, University of Montreal, QC, Canada; 4 Neurobiological Psychiatry Unit, McGill University, Montreal, QC, Canada; 5 Pharmaceutical Dept. University of Parma, Italy
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| Content: | Melatonin is a neurohormone implicated in the regulation of sleep and circadian rhythms and binds two G-protein coupled brain receptors, MT1 and MT2. The differential role of these two receptors in sleep function is completely unknown. Here we propose a novel drug acting as an MT2 receptor partial agonist, called UCM765 (N-{2-[(3-Methoxyphenyl)-phenylamino]ethyl}acetamide), with a 100-fold higher affinity for the human recombinant receptor MT2 (pKi = 10.18) than for MT1 (pKi = 8.28) .
In order to test the sleep-promoting properties of UCM765, we recorded electroencephalogram (EEG) and electromyogram (EMG) in freely-moving rats (n=7-11 for each set of experiments) from 6:00-9:00 PM following a subcutaneous injection of vehicle, diazepam (2mg/kg) or UCM765 (40mg/kg). Rats treated with UCM765 exhibited a shorter latency (min) of onset of the first slow wave sleep (SWS) episode compared to control (ctrl: 24.3 ± 2.8; UCM 765: 14.2 ± 2.6, p<0.05) similar to diazepam (11.8 ± 2.5). The UCM 765 also increased the duration (min) of the SWS (ctrl: 58.1 ± 3.2; UCM765: 88.3 ± 3.2, p<0.05; diazepam: 92.0 ± 4.4, p<0.05). Then, we administered the selective MT2 antagonist 4-PPDOT (10mg/kg) prior to UCM765. The antagonist 4-PPDOT blocked the effects on the latency of SWS (ctrl: 29.6 ± 3.3; UCM765: 16.9 ± 2.7; UCM765 + 4-PPDOT: 22.4 ± 2.6; p=0.02) as well on the duration of SWS (ctrl: 53.7 ± 4.1; UCM765: 72.4 ± 5.0; UCM756 + 4-PPDOT: 57.4 ± 5.7 p=0.006). Results for paradoxical sleep (PS, or REM sleep) indicate that UCM765, prolonged the latency of the first episode of PS (ctrl: 49.7 ± 4.1; UCM765: 75.1 ± 5.9, p<0.05; diazepam: 74.5 ± 5.2, p<0.05), similar to diazepam, but did not change the duration or quantity of PS episodes. Next, we assessed the properties of UCM765 (40 mg/kg, six times per day, every 4 hours) across 24 hours. Remarkably, the 24-hour EEG and EMG showed that UCM765 increases SWS only during the inactive or light phase (the period of sleep for rats) (ctrl: 279.6 ± 44.5; UCM765: 414 ± 12.4; p=0.006) and not during the active or dark phase (ctrl: 187.4 ± 11.2; UCM765: 228.9 ± 26.1). Finally, we carried out experiments on MT2 knockout (KO) and wildtype mice. The UCM765 decreases the latency (WT: 23.6 ± 3.3; WT-UCM765: 13.5 ± 2.1, p<0.05) and increases the duration of SWS (WT: 62.0 ± 5.6; WT-UCM765: 84.1 ± 8.0) in wildtype mice; but did not changes the latency (KO: 27.9 ± 6.2; KO-UCM765: 20.0 ± 1.4, p<0.05) and duration (KO: 50.9 ± 4.0; KO-UCM765: 48.8 ± 4.0) of SWS in MT2 KO mice; remarkably, MT2 KO mice |
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