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Clinical studies indicate that cannabidiol (CBD), the primary nonaddictive component of cannabis that interacts with the serotonin (5-HT)1A receptor, may possess analgesic and anxiolytic effects. However, its effects on 5-HT neuronal activity, as well as its impact on models of neuropathic pain are unknown. First, using in vivo single-unit extracellular recordings in rats, we demonstrated that acute intravenous (i.v.) increasing doses of CBD (0.1-1.0 mg/kg) decreased the firing rate of 5-HT neurons in the dorsal raphe nucleus, which was prevented by administration of the 5-HT1A antagonist WAY 100635 (0.3 mg/kg, i.v.) and the TRPV1 antagonist capsazepine (1 mg/kg, i.v.) but not by the CB1 receptor antagonist AM 251 (1 mg/kg, i.v.). Repeated treatment with CBD (5 mg/kg/day, subcutaneously [s.c.], for 7 days) increased 5-HT firing through desensitization of 5-HT1A receptors. Rats subjected to the spared nerve injury model for 24 days showed decreased 5-HT firing activity, mechanical allodynia, and increased anxiety-like behavior in the elevated plus maze test, open-field test, and novelty-suppressed feeding test. Seven days of treatment with CBD reduced mechanical allodynia, decreased anxiety-like behavior, and normalized 5-HT activity. Antiallodynic effects of CBD were fully prevented by capsazepine (10 mg/kg/day, s.c., for 7 days) and partially prevented by WAY 100635 (2 mg/kg/day, s.c., for 7 days), whereas the anxiolytic effect was blocked only by WAY. Overall, repeated treatment with low-dose CBD induces analgesia predominantly through TRPV1 activation, reduces anxiety through 5-HT1A receptor activation, and rescues impaired 5-HT neurotransmission under neuropathic pain conditions.

Translation of mRNA into protein has a fundamental role in neurodevelopment, plasticity, and memory formation; however, its contribution in the pathophysiology of depressive disorders is not fully understood. We investigated the involvement of MNK1/2 (MAPK-interacting serine/threonine-protein kinase 1 and 2) and their target, eIF4E (eukaryotic initiation factor 4E), in depression-like behavior in mice. Mice carrying a mutation in eIF4E for the MNK1/2 phosphorylation site (Ser209Ala, Eif4e ki/ki), the Mnk1/2 double knockout mice (Mnk1/2 -/- ), or mice treated with the MNK1/2 inhibitor, cercosporamide, displayed anxiety- and depression-like behaviors, impaired serotonin-induced excitatory synaptic activity in the prefrontal cortex, and diminished firing of the dorsal raphe neurons. In Eif4e ki/ki mice, brain IκBα, was decreased, while the NF-κB target, TNFα was elevated. TNFα inhibition in Eif4e ki/ki mice rescued, whereas TNFα administration to wild-type mice mimicked the depression-like behaviors and 5-HT synaptic deficits. We conclude that eIF4E phosphorylation modulates depression-like behavior through regulation of inflammatory responses.

Melatonin (MLT) levels fluctuate according to the external light/dark cycle in both diurnal and nocturnal mammals. We previously demonstrated that melatonin MT2 receptor knockout (MT2−/−) mice show a decreased nonrapid eye movement sleep over 24 hours and increased wakefulness during the inactive (light) phase. Here, we investigated the role of MT2 receptors in physiological light/dark cycle fluctuations in the activity of dorsal raphe nucleus (DRN) serotonin (5‐HT) neurons and anxiety‐ and depression‐like behavior. We found that the 5‐HT burst‐firing activity was tonically reduced across the whole 24 hours in MT2−/− mice compared with MT2+/+ mice. Importantly, the physiological changes in the spontaneous firing activity of DRN 5‐HT neurons during the light/dark cycle were nullified in MT2−/− mice, with a higher DRN 5‐HT neural firing activity during the light phase in MT2−/− than in MT2+/+ mice. The role of MT2 receptors over DRN 5‐HT neurons was confirmed by acute pharmacological studies in which the selective MT2 receptors agonist UCM1014 dose dependently inhibited DRN 5‐HT activity, mostly during the dark phase. Compared with MT2+/+, MT2−/− mice displayed an anxiety‐like phenotype in the novelty‐suppressed feeding and in the light/dark box tests; while anxiety levels in the light/dark box test were lower during the dark than during the light phase in MT2+/+ mice, the opposite was seen in MT2−/− mice. No differences between MT2+/+ and MT2−/− mice were observed for depression‐like behavior in the forced swim and in the sucrose preference tests. These results suggest that MT2 receptor genetic inactivation impacts 5‐HT neurotransmission and interferes with anxiety levels by perturbing the physiologic light/dark pattern. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Melatonin (MLT) is a neurohormone known to be involved in the regulation of anxiety. Most of the physiological actions of MLT in the brain are mediated by two high-affinity G-protein-coupled receptors, denoted MT1 and MT2. However, the particular role of these receptors in anxiety remains to be defined. Here we used a novel MT2-selective partial agonist, UCM765 to evaluate the involvement of MT2 receptors in anxiety. Adult male rats were acutely injected with UCM765 (5–10–20mg/kg), MLT (20mg/kg) or diazepam (DZ, 1mg/kg). Anxiety-related behaviors were assessed in the elevated plus maze test (EPMT), novelty suppressed feeding test (NSFT) and open field test (OFT). UCM765 at the dose of 10mg/kg showed anxiolytic-like properties by increasing the time spent in the open arm of the EPMT, and by reducing the latency to eat in a novel environment in the NSFT. In the EPMT, animals treated with UCM765 (10mg/kg) or MLT (20mg/kg) spent more time in the open arms compared to vehicle-treated animals, but to a lesser extent compared to DZ (1mg/kg). In the NSFT, all treatments similarly decreased the latency to eat in a novel environment compared to vehicle. UCM765 and MLT did not affect the total time and the number of entries into the central area of the OFT, but unlike DZ, did not impair locomotion. The anxiolytic effects of UCM765 and MLT in the EPMT and the NSFT were blocked using a pre-treatment with the MT1/MT2 antagonist luzindole (10mg/kg) or the MT2 antagonist 4P-PDOT (10mg/kg). These results demonstrated, for the first time, the anxiolytic properties of UCM765 and suggest that MT2-receptors may be considered a novel target for the development of anxiolytic drugs. [Copyright &y& Elsevier]

• Lower Kyn levels are associated with higher depressive symptoms in pregnancy. • Prenatal Trp levels moderate the link between IL-6 and perinatal depressive symptoms. • Prenatal Kyn/Trp moderates the link between IL-6 and perinatal depressive symptoms. • No interactions among Trp biomarkers and cortisol on perinatal depressive symptoms. • No interactions among Trp biomarkers, IL-6 or cortisol on perinatal anxiety symptoms. Depression and anxiety symptoms are highly prevalent among women during pregnancy and post-partum. Previous studies suggest that one of the pathophysiological underpinnings could be an enhanced metabolism of tryptophan (Trp) into kynurenine (Kyn) due to increased inflammation. However, the longitudinal changes in the Kyn pathway and the complex interplay with inflammation and stress in women with perinatal depressive or anxiety symptoms are incompletely understood. We examined a cohort of healthy women at 34–36 gestational weeks. One hundred and ten women were assessed for salivary cortisol and 97 participants were also assessed for serum levels of Trp, Kyn and Interleukin 6 (IL-6). Women filled in two screening questionnaires for depressive (Edinburgh Postnatal Depression Scale (EPDS)) and anxiety (State Trait Anxiety Inventory subscale (STAI-S)) symptoms at 34–36 gestational weeks, delivery, 3 and 12 months postpartum. Unexpectedly, lower prenatal Kyn levels were associated with higher depressive symptoms in late pregnancy. Furthermore, prenatal Trp levels and the Kyn/Trp ratio moderate the association between IL-6 levels and depressive symptoms during the perinatal and the post-partum period. We found no interactions between Trp and Kyn biomarkers and cortisol on depressive symptoms. The observed associations were more robustly found for depressive symptoms, whereas weak and non-significant effects were found for the trajectory of anxiety symptoms. Overall, our data support the involvement of the Trp to Kyn pathway and inflammation in the course of depressive but not anxiety symptoms in women from late pregnancy until one-year post-partum, providing new evidence on the mechanisms regulating emotions during pregnancy and after delivery in a low-risk sample. [ABSTRACT FROM AUTHOR]