anxiety assessments were observed for ACT-539313. Besides reports of stress related to the challenge, the most frequently reported adverse events were somnolence and headache. No clinically relevant effects in other safety assessments were observed. Multiple-dose administration of ACT-539313 was safe and well tolerated up to multiple doses of 200mg b.i.d. The drug's PK properties as well as the pattern of a decrease in stress-related symptoms after the CO challenge support further investigations of ACT-539313.Multiple-dose administration of ACT-539313 was safe and well tolerated up to multiple doses of 200 mg b.i.d. The drug's PK properties as well as the pattern of a decrease in stress-related symptoms after the CO2 challenge support further investigations of ACT-539313.Despite the important advances in the understanding of the pathophysiology of MDD, a large proportion of depressed patients do not respond well to currently available pharmacological agents. The present review focuses on new targets and future directions in the pharmacological treatment of MDD. Novel agents and their efficacy in the treatment of depression are discussed, with a focus on the respectively target pathophysiological pathways and the level of available evidence. Although it is expected that classic antidepressants will remain the cornerstone of MDD treatment, at least for the near future, a large number of novel compounds is currently under investigation as for their efficacy in the treatment of MDD, many of which with promising results.The lateral hypothalamus (LH) is a diencephalic structure that has been considered part of the central circuitry regulating the baroreflex function. However, the local neurochemical mechanisms involved in baroreflex control by this hypothalamic area are poorly understood. Therefore, in the present study we investigated the role of corticotropin-releasing factor (CRF) neurotransmission within the LH acting via local CRF1 and CRF2 receptors in cardiac baroreflex responses in unanesthetized rats. For this, the baroreflex activity was assessed using two approaches i) the pharmacological approach via intravenous infusion of vasoactive agents, and ii) the sequence analysis technique that evaluates reflex responses during spontaneous arterial pressure variations. The sequence analysis technique indicated that LH treatment with the selective CRF1 receptor antagonist CP376395 decreased the baroreflex effectiveness index, whereas the selective CRF2 receptor antagonist antisauvagine-30 increased the reflex shortening of pulse interval during spontaneous arterial pressure decreases. However, the pharmacological approach did not indicate effect of the bilateral microinjection of either CP376395 or antisauvagine-30 into the LH in the tachycardia evoked by blood pressure decrease or the reflex bradycardia caused by blood pressure increase. Overall, these findings indicate that CRF neurotransmission within the LH controls baroreflex function during a narrow range of physiological arterial pressure variations. Besides, results provide evidence that CRF1 and CRF2 receptors in the LH oppositely modulate the spontaneous baroreflex activity through different mechanisms.It has been observed that, in patients affected by temporomandibular disorders (TMDs) and edentulism, a left-right asymmetry in electromyographic (EMG) activity of masseter muscles during clenching and in pupil size at rest (anisocoria) is present. MEK pathway Both are greatly reduced by an orthotic-prosthetic correction. In parallel, the correction significantly improves cognitive performance. These effects are possibly due to the recovery of a cortical balance, via Locus Coeruleus (LC) modulation, whose activity is powerfully affected by the sensorimotor trigeminal input. The role of this functional axis was further investigated in subjects without overt occlusal or dental problems. In these individuals, the EMG asymmetry was significantly correlated to anisocoria at rest, with the dental arches open or in contact. Also in normal subjects, both the EMG and the pupil asymmetry during clenching could be significantly reduced by an orthotic (bite) correction. Closing the arches without bite increased anisocoria and reduced performance in the Spinnler-Tognoni matrices test, as well as the mydriasis induced by a haptic task. When the bite was interposed, anisocoria was reduced, while both performance and task-related mydriasis were enhanced. Since pupil size is considered a proxy of the LC activity, these results suggest that asymmetric occlusion biases the LC discharge and the hemispheric excitability, possibly via a sensorimotor trigeminal imbalance. Removing the anisocoria through bite correction re-establishes a symmetric LC discharge, improving performance and enhancing task-related mydriasis. Therefore, occlusal balancing may represent a tool for improving subjective performance and may be exploited for training and rehabilitative purposes.Acute ischemic stroke (AIS) causes both central and peripheral inflammation, while activation of α7 nicotinic acetylcholine receptors (nAChRs) provides both central and peripheral anti-inflammatory and anti-apoptotic effects. Here, we provide evidence that 4OH-GTS-21, a selective α7 agonist, produces its therapeutic effects via primarily central sites of action because 4OH-GTS-21 was found equally effective in splenectomized and non-spenectomized rats in the sub-acute phase of ischemic stroke (≤1 week). However, the spleen may boost the therapeutic efficacy of 4OH-GTS-21 in certain behavioral tasks as our data also indicated. In our tests, AIS was modeled by transient middle cerebral artery occlusion (tMCAO). Splenectomy was done 2 weeks before tMCAO. We determined that 1) Daily 4OH-GTS-21 treatments for 7 days after tMCAO significantly reduced neurological deficits and brain injury in both splenectomized and non-spelenectomized rats demonstrating that the spleen is not required for therapeutic benefits of 4OH-GTS-21; 2) The effects of 4OH-GTS-21 in the adhesive sticker removal test were significantly weaker in splenectomized animals suggesting that the spleen boosts the efficacy of 4OH-GTS-21 in the first week after tMCAO; and 3) Ischemic brain injury was not significantly affected by splenectomy in both vehicle-treated and 4OH-GTS-21-treated animals. These data support the hypothesis that the therapeutic efficacy of sub-chronic (≤1 week) 4OH-GTS-21 primarily originates from central sites of action. These results validate brain availability as a critical factor for developing novel α7 ligands for AIS.