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Cannabidiol (CBD) is a cannabinoid component of marijuana that has no significant activity at cannabinoid receptors or psychoactive effects. There is considerable interest in CBD as a therapy for epilepsy. Almost a third of epilepsy patients are not adequately controlled by clinically available anti-seizure drugs (ASDs). Initial studies appear to demonstrate that CBD preparations may be a useful treatment for pharmacoresistant epilepsy. The National Institute of Neurological Disorders and Stroke (NINDS) funded Epilepsy Therapy Screening Program (ETSP) investigated CBD in a battery of seizure models using a refocused screening protocol aimed at identifying pharmacotherapies to address the unmet need in pharmacoresistant epilepsy. Applying this new screening workflow, CBD was investigated in mouse 6 Hz 44 mA, maximal electroshock (MES), corneal kindling models and rat MES and lamotrigine-resistant amygdala kindling models. Following intraperitoneal (i.p.) pretreatment, CBD produced dose-dependent protection in the acute seizure models; mouse 6 Hz 44 mA (ED 50 164 mg/kg), mouse MES (ED 50 83.5 mg/kg) and rat MES (ED 50 88.9 mg/kg). In chronic models, CBD produced dose-dependent protection in the corneal kindled mouse (ED 50 119 mg/kg) but CBD (up to 300 mg/kg) was not protective in the lamotrigine-resistant amygdala kindled rat. Motor impairment assessed in conjunction with the acute seizure models showed that CBD exerted seizure protection at non-impairing doses. The ETSP investigation demonstrates that CBD exhibits anti-seizure properties in acute seizure models and the corneal kindled mouse. However, further preclinical and clinical studies are needed to determine the potential for CBD to address the unmet needs in pharmacoresistant epilepsy.

Psychosis is a syndrome embedded in several disorders, including schizophrenia and bipolar disorder with psychotic features. Dopamine and glutamate are implicated in the pathophysiology of psychotic symptoms. Psychosocial treatments supplement pharmacologic therapy.

The assessment of the efficacy of antiseizure medications (ASMs) in animal models of acute seizures has played a critical role in these drugs’ success in clinical trials for human epilepsy. One of the most widely used animal models for this purpose is the maximal electroshock seizure (MES) model. While there are numerous published reports on the efficacy of conventional ASMs in MES models, there is a need to expand the understanding on the brain concentrations that are needed to achieve optimal levels of efficacy in this model. We assessed the pharmacokinetic/pharmacodynamic (PK/PD) profiles of six ASMs, namely carbamazepine (CBZ), phenytoin (PHT), valproic acid (VPA), lacosamide (LSM), cenobamate (CNB), and retigabine (RTG), using MES models in mice and rats. EC50 values for plasma and the brain were generally higher in mice than rats, with fold differences ranging from 1.3- to 8.6-fold for plasma and from 1.2- to 11.5-fold for brain. Phenytoin showed the largest interspecies divergence. These results suggest that rats may exhibit greater sensitivity to seizure protection in the MES model, likely reflecting species differences in metabolism and brain penetration. These findings highlight the value of considering concentration–response variations and species-specific differences when assessing the efficacy of both conventional ASMs and novel compounds exhibiting anticonvulsant activity.

The transcription factor Keap1–Nrf2 signaling plays a key role in the oxidative stress which is involved in psychiatric disorders. In the learned helplessness (LH) paradigm, protein levels of Keap1 and Nrf2 in the prefrontal cortex and dentate gyrus of hippocampus from LH (susceptible) rats were lower than control and non-LH (resilience) rats. Furthermore, protein expressions of Keap1 and Nrf2 in the parietal cortex from major depressive disorder, schizophrenia, and bipolar disorder were lower than controls. These results suggest that Keap1–Nrf2 signaling might contribute to stress resilience which plays a key role in the pathophysiology of psychiatric disorders.

Objective Intestinal permeability and psychological stress have been implicated in the pathophysiology of IBD and IBS. Studies in animals suggest that stress increases permeability via corticotropin-releasing hormone (CRH)-mediated mast cell activation. Our aim was to investigate the effect of stress on intestinal permeability in humans and its underlying mechanisms. Design Small intestinal permeability was quantified by a 2 h lactulose–mannitol urinary excretion test. In a first study, 23 healthy volunteers were subjected to four different conditions: control; indomethacin; public speech and anticipation of electroshocks. In a second study, five test conditions were investigated in 13 volunteers: control; after pretreatment with disodium cromoglycate (DSCG); administration of CRH; DSCG+CRH and DSCG+public speech. Results Indomethacin, as a positive comparator (0.071±0.040 vs 0.030±0.022; p<0.0001), and public speech (0.059±0.040; p<0.01), but not the shock protocol increased intestinal permeability. Similarly, salivary cortisol was only increased after public speech. Subgroup analysis demonstrated that the effect of public speech on permeability was only present in subjects with a significant elevation of cortisol. CRH increased the lactulose–mannitol ratio (0.042±0.021 vs 0.028±0.009; p=0.02), which was inhibited by the mast cell stabiliser DSCG. Finally, intestinal permeability was unaltered by public speech with DSCG pretreatment. Conclusions Acute psychological stress increases small intestinal permeability in humans. Peripheral CRH reproduces the effect of stress and DSCG blocks the effect of both stress and CRH, suggesting the involvement of mast cells. These findings provide new insight into the complex interplay between the central nervous system and GI function in man.

Agetsuma and colleagues find that the pathway between the lateral subnucleus of the dorsal habenula (dHbL) and the interpeduncular nucleus is involved in mediating experience-dependent fear responses in zebrafish. Genetic inactivation of the dHbL biased fish towards freezing, rather than the typical flight behavior, in response to a conditioned fear stimulus. The zebrafish dorsal habenula (dHb) shows conspicuous asymmetry in its connection with the interpeduncular nucleus (IPN) and is equivalent to the mammalian medial habenula. Genetic inactivation of the lateral subnucleus of dHb (dHb L ) biased fish towards freezing rather than the normal flight response to a conditioned fear stimulus, suggesting that the dHb L -IPN pathway is important for controlling experience-dependent modification of fear responses.

Animals must respond to various threats to survive. Neurons that express calcitonin gene-related peptide in the parabrachial nucleus (CGRP PBN neurons) relay sensory signals that contribute to satiation and pain-induced fear behaviour, but it is unclear how they encode these distinct processes. Here, by recording calcium transients in vivo from individual neurons in mice, we show that most CGRP PBN neurons are activated by noxious cutaneous (shock, heat, itch) and visceral stimuli (lipopolysaccharide). The same neurons are inhibited during feeding, but become activated during satiation, consistent with evidence that CGRP PBN neurons prevent overeating. CGRP PBN neurons are also activated during consumption of novel foods or by an auditory cue that has previously been paired with electrical footshocks. Correspondingly, silencing of CGRP PBN neurons attenuates the expression of food neophobia and conditioned fear responses. Therefore, in addition to transducing primary sensory danger signals, CGRP PBN neurons promote affective-behavioural states that limit harm in response to potential threats. Single-cell recordings show that CGRP-expressing neurons in the parabrachial nucleus in mice respond to both noxious stimuli and signals of feeding satiety. A brain switchboard for danger CGRP-expressing neurons in the parabrachial nucleus (PBN) in the brain relay signals that drive behaviours as diverse as food consumption and avoidance responses to pain. However, how these various distinct behaviours are encoded or monitored is not known. Carlos Campos and colleagues followed the activity of individual PBN CGRP-expressing neurons in mice and determined that most of these cells respond to both feeding-satiety signals and noxious stimuli. These findings suggest that PBN CGRP-expressing neurons transduce primary 'danger' signals, which promotes affective behaviours that help individuals to avoid harmful threats such as overeating or pain, limiting harm.

The objective of this study is to evaluate the anticonvulsant efficacy of carbamazepine (CBZ) following acute and chronic administration across four treatment protocols in a murine model of maximal electroshock-induced seizures. A single dose of the drug was utilized as a control. The neurotoxic effects were evaluated in the chimney test and the passive avoidance task. Furthermore, plasma and brain concentrations of CBZ were quantified across all treatment protocols. The subchronic administration of CBZ (7 × 2 protocol) resulted in an attenuation of its antielectroshock effect. In the three remaining treatment regimens (7 × 1, 14 × 1, and 14 × 2) the median effective doses of CBZ were comparable to the control. Neither acute nor chronic treatment with CBZ resulted in a discernible impact on motor coordination or long-term memory. The plasma and brain concentrations of CBZ were significantly lower in most chronic protocols when compared to a single-dose application. This may explain the transient attenuation of CBZ effectiveness in the 7 × 2 protocol, but not the return to the previous level. The anticonvulsant and neurotoxic profiles of CBZ did not differ after single and chronic administration. Therefore, experimental chronic studies with CBZ are not prerequisites for concluding and possibly translating results to clinical conditions.

Su et al . investigated the chromatin accessibility status of neurons in the adult mouse dentate gyrus at different timepoints after activation at the genome-wide level. Their study provides a potential mechanism by which neuronal activity may reshape the epigenetic landscape, thereby dynamically changing transcriptome and neuronal properties over time. Neuronal activity-induced gene expression modulates the function and plasticity of the nervous system. It is unknown whether and to what extent neuronal activity may trigger changes in chromatin accessibility, a major mode of epigenetic regulation of gene expression. Here we compared chromatin accessibility landscapes of adult mouse dentate granule neurons in vivo before and after synchronous neuronal activation using an assay for transposase-accessible chromatin using sequencing (ATAC-seq). We found genome-wide changes 1 h after activation, with enrichment of gained-open sites at active enhancer regions and at binding sites for AP1-complex components, including c-Fos. Some changes remained stable for at least 24 h. Functional analysis further implicates a critical role of c-Fos in initiating, but not maintaining, neuronal activity-induced chromatin opening. Our results reveal dynamic changes of chromatin accessibility in adult mammalian brains and suggest an epigenetic mechanism by which transient neuronal activation leads to dynamic changes in gene expression via modifying chromatin accessibility.