Selective Enhancement of REM Sleep in Male Rats through Activation of MT1 Receptors Located in the Locus Coeruleus Norepinephrine neurons.

Sleep disorders affect millions of people around the world and have a high comorbidity with psychiatric disorders. While current hypnotics mostly increase non-rapid eye movement sleep (NREMS), drugs acting selectively on enhancing rapid eye movement sleep (REMS) are lacking. This polysomnographic study in male rats showed that the first-in-class selective melatonin MT1 receptor partial agonist UCM871 increases the duration of REMs without affecting that of NREMS. The REMS-promoting effects of UCM871 occurred by inhibiting, in a dose-response manner, the firing activity of the locus coeruleus (LC) norepinephrine (NE) neurons, which express MT1 receptors. The increase of REMS duration and the inhibition of LC-NE neuronal activity by UCM871 were abolished by MT1 pharmacological antagonism and by an adeno-associated viral (AAV) vector which selectively knocked down MT1 receptors in the LC-NE neurons. In conclusion, MT1 receptor agonism inhibits LC-NE neurons and triggers REMS, thus representing a novel mechanism and target for REMS disorders and/or psychiatric disorders associated with REMS impairments.Significance Statement Rapid eye movement sleep (REMS) is involved in the processes of memory consolidation and emotional regulation, but drugs selectively enhancing REMS are scant. Herein, we show that the first-in-class selective melatonin MT1 receptor agonist UCM871, by inhibiting the activity of norepinephrine neurons in the locus coeruleus, an important nucleus regulating the sleep/wake cycle, selectively increases the duration of REMS. These findings enhance our current understanding of the neurobiology and pharmacology of REMS and provide a possible novel mechanism and target for disorders associated with REMS dysfunctions.

Frequent follow-up of suicidal youth assessed in the emergency room: Long-term trajectory and predictors of suicidality.

Suicide was the second­leading cause of US deaths in 2018 among 15-24-year-olds. Suicide attempts, a risk factor for completions, and suicide ideation have doubled among pediatric emergency room (ER) patients during the past decade. Borderline Personality Disorder (BPD), a comorbid condition, has a 10% suicide rate. We examined the 4-year outcome of a cohort of suicidal adolescents, many also suffering from BPD and having undergone some form of treatment, to identify baseline factors which could inform intervention that would minimize suicidality 4 years post-discharge. METHODS: We conducted a prospective longitudinal study of suicidality at twelve points (four assessment occasions) for 286 suicidal youth presenting to a pediatric ER, most suffering from BPD, with 36 suicide ratings from baseline to 2-, 6- and 48-month follow-up evaluations. We examined the trajectory and predictors of persisting suicidality. RESULTS: Suicidality rapidly decreased within 2 months post-ER-discharge, subsequently remaining low throughout 48 months. Baseline functioning, female sex, stressful life events and BPD impulsiveness were most predictive of persisting suicidality at 48-month follow-up. CONCLUSION: Most suicidal youth, many meeting BPD criteria, no longer feel suicidal 2 months after ER discharge. Management of participants' baseline poor functioning stressful life events and the impulsiveness component of BPD specifically in females could impact suicidality 4 years later, and guide treatment options. The absence of the BPD cognitive and affective subscales as predictors of suicidality at 4-year follow-up may reflect treatment received. Further investigation of treatment effects is warranted and under way.