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Administration of Cannabis sativa derivatives causes anxiolytic or anxiogenic effects in humans and laboratory animals, depending on the specific compound and dosage used. In agreement with these findings, several studies in the last decade have indicated that the endocannabinoid system modulates neuronal activity in areas involved in defensive responses. The mechanisms of these effects, however, are still not clear. The present review summarizes recent data suggesting that they involve modulation of glutamate and GABA-mediated neurotransmission in brain sites such as the medial prefrontal cortex, amygdaloid complex, bed nucleus of the stria terminalis, hippocampus and dorsal periaqueductal gray. Moreover, we also discuss results indicating that, in these regions, the endocannabinoid system could be particularly engaged by highly stressful situations. [ABSTRACT FROM PUBLISHER]

Background and Purpose: Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa that induces anxiolytic- and antipsychotic-like effects in animal models. Effects of CBD may be mediated by the activation of 5-HT(1A) receptors. As 5-HT(1A) receptor activation may induce antidepressant-like effects, the aim of this work was to test the hypothesis that CBD would have antidepressant-like activity in mice as assessed by the forced swimming test. We also investigated if these responses depended on the activation of 5-HT(1A) receptors and on hippocampal expression of brain-derived neurotrophic factor (BDNF).Experimental Approach: Male Swiss mice were given (i.p.) CBD (3, 10, 30, 100 mg*kg(-1)), imipramine (30 mg*kg(-1)) or vehicle and were submitted to the forced swimming test or to an open field arena, 30 min later. An additional group received WAY100635 (0.1 mg*kg(-1), i.p.), a 5-HT(1A) receptor antagonist, before CBD (30 mg*kg(-1)) and assessment by the forced swimming test. BDNF protein levels were measured in the hippocampus of another group of mice treated with CBD (30 mg*kg(-1)) and submitted to the forced swimming test.Key Results: CBD (30 mg*kg(-1)) treatment reduced immobility time in the forced swimming test, as did the prototype antidepressant imipramine, without changing exploratory behaviour in the open field arena. WAY100635 pretreatment blocked CBD-induced effect in the forced swimming test. CBD (30 mg*kg(-1)) treatment did not change hippocampal BDNF levels.Conclusion and Implications: CBD induces antidepressant-like effects comparable to those of imipramine. These effects of CBD were probably mediated by activation of 5-HT(1A) receptors. [ABSTRACT FROM AUTHOR]

The endocannabinoid system has been proposed to modulate neuronal functions involved in distinct types of defensive reactions, possibly counteracting the harmful consequences of stressful stimuli. However, the precise brain sites for this action remain to be further explored. This chapter summarizes the data about the role of the endocannabinoid system in the processing of conditioned fear as well as the potential neural subtract for its actions. [ABSTRACT FROM AUTHOR]

Lead absorption is influenced by the species that are formed and the physicochemical characteristics of lead, among others. Lead plasma concentration is < 5% of total blood lead and represents the biologically active fraction able to cross the cell membranes. Health risks mainly depend on a specific metal and its species. Speciation analysis is the analytical activity of identifying and determining different metal species. Chromatographic methods are very useful in the identification of species and the techniques most used to determine metals in biological fluids are ICP OES/MS and AAS. Lead speciation analysis in blood plasma is fundamental for understanding and evaluating the interaction mechanisms between that analyte and its biological targets.

Apesar de a mineração de bauxita causar grandes alterações nas características do solo, com efeitos negativos nas micorrizas arbusculares, os efeitos da reabilitação de áreas mineradas sobre os fungos micorrízicos arbusculares (MA) e sua simbiose são pouco conhecidos. O objetivo deste trabalho foi avaliar a ocorrência, diversidade e eficiência dos fungos MA, em áreas de mineração de bauxita, com diferentes tipos de vegetação e idades de reabilitação. Amostras de solo da rizosfera foram coletadas para analisar o micélio fúngico extrarradicular, o número de esporos, a riqueza e diversidade de fungos MA e para avaliar a colonização micorrízica e eficiência simbiótica de populações fúngicas. A mineração afetou negativamente os fungos MA, sendo a recuperação destes mais relacionada com o tipo de vegetação do que com o tempo de reabilitação da área. Foram encontradas as espécies: Gigaspora margarita, Gigaspora sp., Paraglomus occultum, Glomus sp., Entrophospora colombiana e Acaulospora scrobiculata. A ocorrência desses fungos foi favorecida pela presença de gramíneas ede bracatinga. Embora Eucalyptus saligna não seja um bom hospedeiro para os fungos MA, quando associado a sub-bosque bem desenvolvido e diverso, contribuiu para a recuperação dos fungos. As populações fúngicas isoladas de áreas com braquiária e feijão-guandu ou de bracatinga com capim-gordura apresentaram elevada eficiência para o feijoeiro, mostrando que é possível recuperar a função deste grupo de microrganismos utilizando diferentes tipos de vegetação. Estes isolados apresentam potencial de utilização em programas de reabilitação de solos minerados.

O objetivo deste trabalho foi avaliar, em casa de vegetação, o comportamento de espécies herbáceas em relação ao excesso de Cd e Zn no solo. O gradiente de contaminação foi estabelecido a partir de mistura de solo contaminado com solo sem contaminação em diferentes proporções. As sementes foram semeadas em tubetes contendo 250 mL de solo, e após 90 dias as plantas foram colhidas e avaliadas. A maioria das espécies apresentou redução no crescimento com aumento da contaminação do solo e elevadas concentrações de Cd e Zn na matéria seca da parte aérea (MSPA), na mistura com 15% de solo contaminado. A espécie Pffafia sp. mostrou-se tolerante à contaminação, crescendo em misturas de solo contendo até 90 mg kg-1 de Cd e 1.450 mg kg-1 de zinco. Além disso, apresentou concentração superior a 100 mg kg-1 de Cd na MSPA, sendo considerada hiperacumuladora desse metal. Sida glaziovii, Bidens pilosa, Rhynchelytrum repens, Cenchrus echinatus e Nicandra physaloides, por sua vez, foram severamente afetadas pela contaminação, ao contrário de Trifolium repens, Euchlaena mexicana, Cynodon dactylon, Avena strigosa, Cenchrus ciliares e Cyperus sp. que apresentaram crescimento satisfatório. As espécies avaliadas mostram-se promissoras para estudos adicionais sobre a reabilitação de áreas contaminadas com metais pesados.

Objective: The transient receptor potential cation channel, subfamily V (vanilloid), member 1 (TRPV1) mediates pain perception to thermal and chemical stimuli in peripheral neurons. The cannabinoid receptor type 1 (CB 1 ), on the other hand, promotes analgesia in both the periphery and the brain. TRPV1 and CB 1 have also been implicated in learned fear, which involves the association of a previously neutral stimulus with an aversive event. In this review, we elaborate on the interplay between CB 1 receptors and TRPV1 channels in learned fear processing., Methods: We conducted a PubMed search for a narrative review on endocannabinoid and endovanilloid mechanisms on fear conditioning., Results: TRPV1 and CB 1 receptors are activated by a common endogenous agonist, arachidonoyl ethanolamide (anandamide), Moreover, they are expressed in common neuroanatomical structures and recruit converging cellular pathways, acting in concert to modulate fear learning. However, evidence suggests that TRPV1 exerts a facilitatory role, whereas CB 1 restrains fear responses., Conclusion: TRPV1 and CB 1 seem to mediate protective and aversive roles of anandamide, respectively. However, more research is needed to achieve a better understanding of how these receptors interact to modulate fear learning.

Objective: Preclinical studies suggest that cannabidiol (CBD), a non-intoxicating phytocannabinoid, may reduce addiction-related behaviours for various drug classes in rodents, including ethanol, opiates, and psychostimulants. CBD modulates contextual memories and responses to reward stimuli. Nonetheless, research on the impact of CBD on cocaine addiction-like behaviors is limited and requires further clarification. This study tested the hypothesis that CBD administration inhibits the acquisition and retrieval of cocaine-induced conditioned place preference (CPP) in adult male and female C57BL6/J mice. We also ought to characterise a 5-day CPP protocol in these animals., Methods: Male and female C57BL/6J mice were administered CBD (3, 10, and 30 mg/kg) 30 minutes before cocaine (15 mg/kg) acquisition of expression of CPP., Results: Cocaine induces a CPP in both female and male mice in the 5-day CPP protocol. CBD failed to prevent the acquisition or retrieval of place preference induced by cocaine. CBD did not decrease the time spent on the side paired with cocaine at any of the doses tested in male and female mice, in either acquisition or expression of contextual memory., Conclusion: This study found no support for the hypothesis that CBD decreases reward memory involved in the formation of cocaine addiction. Further research is necessary to investigate the involvement of CBD in other behavioural responses to cocaine and other psychostimulant drugs. This study, however, characterised a 5-day CPP protocol for both female and male C57BL/6J mice.

Molecular Recognition in nucleotides is crucial for medicine, underpinning precise interactions in genetic replication and therapy. Alkylated nucleotides, in particular, play a key role in modifying DNA to inhibit cancer cell growth. In this study, we focused on an alkylated nucleotide, PNM2 (3',4',6'-O-tristearoyl uridine or uridine tri-stearate), to investigate the interaction between adenine molecules in the aqueous subphase and PNM2 Langmuir monolayers. Utilizing techniques such as tensiometry, Brewster angle microscopy, infrared spectroscopy, surface potential measurements, and dilatational surface rheology, we found compelling evidence of molecular Recognition between the polar head of the insoluble amphiphile (uridine) in the monolayer and adenine in the aqueous subphase, attributed to hydrogen bonding. These interactions significantly influenced the physicochemical properties of the air-water interface, including monolayer expansion upon molecular recognition, decreased dilatational modulus, increased tensiometric stability of the monolayer when compressed to relevant surface pressures, and decreased surface potential. These findings are noteworthy for drug development, providing crucial insights into the mechanisms of nucleotide interactions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Understanding the mechanisms by which drugs interact with cell membranes is crucial for unraveling the underlying biochemical and biophysical processes that occur on the surface of these membranes. Our research focused on studying the interaction between an ester-type derivative of tristearoyl uridine and model cell membranes composed of lipid monolayers at the air-water interface. For that, we selected a specific lipid to simulate nontumorigenic cell membranes, namely 1,2-dihexadecanoyl-sn-glycero-3-phospho-l-serine. We noted significant changes in the surface pressure-area isotherms, with a noticeable shift towards larger areas, which was lower than expected for ideal mixtures, indicating monolayer condensation. Furthermore, the viscoelastic properties of the interfacial film demonstrated an increase in both the elastic and viscous parameters for the mixed film. We also observed structural alterations using vibrational spectroscopy, which revealed an increase in the all-trans to gauche conformers ratio. This confirmed the stiffening effect of the prodrug on the lipid monolayer. In summary, this study indicates that this lipophilic prodrug significantly impacts the lipid monolayer's thermodynamic, rheological, electrical, and molecular characteristics. This information is crucial for understanding how the drug interacts with specific sites on the cellular membrane. It also has implications for drug delivery, as the drug's passage into the cytosol may involve traversing the lipid bilayer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Substance abuse disorder is a chronic condition for which pharmacological treatment options remain limited. L-type calcium channels (LTCC) have been implicated in drug-related plasticity and behavior. Specifically, dopaminergic neurons in the mesocorticolimbic pathway express Ca v 1.2 and Ca v 1.3 channels, which may regulate dopaminergic activity associated with reward behavior. Therefore, this study aimed to investigate the hypothesis that pre-administration of the LTCC blocker, isradipine can mitigate the effects of cocaine by modulating central glutamatergic transmission. For that, we administered isradipine at varying concentrations (1, 7.5, and 15 μg/μL) via intracerebroventricular injection in male Swiss mice. This pretreatment was carried out prior to subjecting animals to behavioral assessments to evaluate cocaine-induced locomotor sensitization and conditioned place preference (CPP). The results revealed that isradipine administered at a concentration of 1 μg/μL effectively attenuated both the sensitization and CPP induced by cocaine (15 mg/kg, via i. p.). Moreover, mice treated with 1 μg/μL of isradipine showed decreased presynaptic levels of glutamate and calcium in the cortex and hippocampus as compared to control mice following cocaine exposure. Notably, the gene expression of ionotropic glutamate receptors, AMPA, and NMDA, remained unchanged, as did the expression of Ca v 1.2 and Ca v 1.3 channels. Importantly, these findings suggest that LTCC blockage may inhibit behavioral responses to cocaine, most likely by decreasing glutamatergic input in areas related to addiction., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study investigated the respiratory activity in adult Wistar rats across different behavioral seizure severity induced by pentylenetetrazole (PTZ). Animals underwent surgery for electrodes implantation, allowing simultaneous EEG and diaphragm EMG (DIA EMG ) recordings and the respiratory frequency and DIA EMG amplitude were measured. Seizures were acutely induced through PTZ injection and classified based on a pre-established score, with absence-like seizures (spike wave discharge (SWD) events on EEG) representing the lowest score. The respiratory activity was grouped into the different seizure severities. During absence-like and myoclonic jerk seizures, the breathing frequency decreased significantly (∼50% decrease) compared to pre- and post-ictal periods. Pronounced changes occurred with more severe seizures (clonic and tonic) with periods of apnea, especially during tonic seizures. Apnea duration was significantly higher in tonic compared to clonic seizures. Notably, during PTZ-induced tonic seizures the apnea events were marked by tonic DIA EMG contraction (tonic-phase apnea). In the majority of animals (5 out of 7) this was a fatal event in which the seizure-induced respiratory arrest preceded the asystole. In conclusion, we provide an assessment of the respiratory activity in the PTZ-induced acute seizures and showed that breathing dysfunction is more pronounced in seizures with higher severity., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Addiction to psychostimulant drugs, such as cocaine, D-amphetamine, and methamphetamine, is a public health issue that substantially contributes to the global burden of disease. Psychostimulant drugs promote an increase in dopamine levels within the mesocorticolimbic system, which is central to the rewarding properties of such drugs. Cannabinoid receptors (CB 1 R and CB 2 R) are expressed in the main areas of this system and implicated in the neuronal mechanisms underlying the rewarding effect of psychostimulant drugs. Here, we reviewed studies focusing on pharmacological intervention targeting cannabinoid CB 1 R and CB 2 R and their interaction in the modulation of psychostimulant responses.

Minocycline is a tetracycline antibiotic with off-label use as an anti-inflammatory drug. Because it can cross the blood-brain barrier, minocycline has been proposed as an alternative treatment for psychiatric disorders, in which inflammation plays an important role. However, its beneficial effects on anxiety disorders are unclear. Therefore, we performed a systematic review and meta-analysis to evaluate the efficacy of minocycline as an anxiolytic drug in preclinical models. We performed a PubMed search according to the PRISMA guidelines and PICOS strategy. The risk of bias was evaluated using the SYRCLE tool. We included studies that determined the efficacy of minocycline in animal models of anxiety that may involve exposures (e.g. stressors, immunomodulators, injury). Data extracted included treatment effect, dose range, route of administration, and potential mechanisms for the anxiolytic effect. Meta-analysis of twenty studies showed that minocycline reduced anxiety-like behavior in rodents previously exposed to stress or immunostimulants but not in exposure-naïve animals. This effect was not associated with the dose administered or treatment duration. The mechanism for the anxiolytic activity of minocycline may depend on its anti-inflammatory effects in the brain regions involving anxiety. These suggest that minocycline could be repurposed as a treatment for anxiety and related disorders and warrants further evaluation., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Cannabidiol (CBD) has been investigated as a pharmacological approach for treating a myriad of neurological and psychiatric disorders, the most successful of them being its use as an antiseizure drug (ASD). Indeed, CBD has reached the clinics for the treatment of certain epileptic syndromes. This chapter aims to overview the pharmacology of CBD and its potential mechanisms of action as an ASD. First, we give an outline of the concepts, mechanisms and pharmacology pertaining to the field of study of epilepsy and epileptic seizures. In the second section, we will summarize the effects of CBD as an ASD. Next, we will discuss its potential mechanisms of action to alleviate epileptic seizures, which seem to entail multiple neurotransmitters, receptors and intracellular pathways. Finally, we will conclude and present some limitations and perspectives for future studies., (Copyright © 2024. Published by Elsevier Inc.)

Cannabidiol (CBD) has been investigated for several therapeutic applications, having reached the clinics for the treatment of certain types of epilepsies. This chapter reviews the potential of CBD for the treatment of substance use disorders (SUD). We will present a brief introduction on SUD and current treatments. In the second part, preclinical and clinical studies with CBD are discussed, focusing on its potential therapeutic application for SUD. Next, we will consider the potential molecular mechanism of action of CBD in SUD. Finally, we will summarize the main findings and perspectives in this field. There is a lack of studies on CBD and SUD in comparison to the extensive literature investigating the use of this phytocannabinoid for other neurological and psychiatric disorders, such as epilepsy. However, the few studies available do suggest a promising role of CBD in the pharmacotherapy of SUD, particularly related to cocaine and other psychostimulant drugs., (Copyright © 2024. Published by Elsevier Inc.)

Cannabis is a general name for plants of the genus Cannabis. Used as fiber, medicine, drug, for religious, therapeutic, and hedonistic purposes along the millenia, it is mostly known for its psychoactive properties. One of its major constituents, cannabidiol (CBD), a non-psychoactive substance, among many other biological activities, has shown potential as an anti-SARS-CoV-2 drug. In this work, three derivatives and an analogue of CBD were synthesized, and cell viability and antiviral activities were evaluated. None of the compounds showed cytotoxicity up to a maximum concentration of 100 μM and, in contrast, displayed a significant antiviral activity, superior to remdesivir and nafamostat mesylate, with IC 50 values ranging from 9.4 to 1.9 μM. In order to search for a possible molecular target, the inhibitory activity of the compounds against ACE2 was investigated, with expressive results (IC 50 ranging from 3.96 μM to 0.01 μM)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

The transient receptor potential vanilloid type-1 (TRPV1) channels have been implicated in the modulation of aversive responses. The endocannabinoid anandamide acts as an endogenous TRPV1 agonist, exerting opposite functions at TRPV1 and type-1 cannabinoid receptors (CB 1 R). Here we tested the hypothesis that hippocampal TRPV1 modulates contextual fear memory retrieval and investigated the influence of the aversive stimulus intensity as well as the role of endocannabinoid signaling. Male C57BL/6J mice were tested for contextual fear memory after low-, moderate-, or high-intensity shock protocols. The selective TRPV1 blockers SB366791 (1-10 nmol) and 6-I-NC (2 nmol) were infused via intra-dorsal hippocampus before the retrieval test session. The local levels of endocannabinoids and Arc and Zif268 mRNAs, involved in synaptic plasticity and memory, were quantified. First, both TRPV1 blockers reduced memory retrieval in animals exposed to moderate or high (but not low) intensity training protocols. In the second series of results, the magnitude of the freezing responses positively correlated with the hippocampal anandamide levels; TRPV1 and CB 1 R were found co-localized in this brain region; and the CB 1 R antagonist, AM251, prevented the effects of SB366791. Thus, endocannabinoid signaling possibly mediates the effects of TRPV1 blockers. Finally, inhibition of memory retrieval by TRPV1 blockers increased Arc and Zif268 mRNAs and impaired fear memory reinstatement. In conclusion, the modulation of fear memories by dorsal hippocampal TRPV1 channels may depend on the aversive stimulus intensity and occur via anandamide/CB 1 signaling. Moreover, TRPV1 blockers promote Arc and Zif268 transcription, with subsequent attenuation of aversive memory reinstatement., (Copyright © 2022. Published by Elsevier Ltd.)

Δ 9 -THC (the main active compound from Cannabis sativa ) and related cannabinoids have been used as drugs of abuse and as medications. They induce a complex set of emotional responses in humans and experimental animals, consisting of either anxiolysis or heightened anxiety. These discrepant effects pose a major challenge for data reproducibility and for developing new cannabinoid-based medicines. In this study, we review and analyze previous data on cannabinoids and anxiety-like behavior in experimental animals. Systematic review and meta-analysis on the effects of type-1 cannabinoid receptor agonists (full or partial, selective or not) in rodents exposed to the elevated plus maze, a widely used test of anxiety-like behavior. Cannabinoids tend to reduce anxiety-like behavior if administered at low doses. THC effects are moderated by the dose factor, with anxiolytic- and anxiogenic-like effects occurring at low-dose (0.075-1 mg/kg) and high-dose (1-10 mg/kg) ranges, respectively. However, some studies report no effect at all regardless of the dose tested. Finally, motor impairment represents a potential confounding factor when high doses are administered. The present analysis may contribute to elucidate the experimental factors underlying cannabinoid effects on anxiety-like behavior and facilitate data reproducibility in future studies.

Background: β-caryophyllene (BCP) is a natural bicyclic sesquiterpene found in Cannabis and other plants. BCP is currently used as a food additive, although pharmacological studies suggest its potential therapeutic application for the treatment of certain brain disorders. The mechanisms of action of BCP remain uncertain, possibly including full agonism at the cannabinoid CB2 receptor (CB2R)., Objective: The study aims to investigate BCP's potential as a new drug for the treatment of substance use disorders by reviewing preclinical studies with animal models., Results: BCP has been investigated in behavioral paradigms, including drug self-administration, conditioned place preference, and intracranial self-stimulation; the drugs tested were cocaine, nicotine, alcohol, and methamphetamine. Remarkably, BCP prevented or reversed behavioral changes resulting from drug exposure. As expected, the mechanism of action entails CB2R activation, although this is unlikely to constitute the only molecular target to explain such effects. Another potential target is the peroxisome proliferator-activated receptor., Conclusion: Preclinical studies have reported promising results with BCP in animal models of substance use disorders. Further research, including studies in humans, are warranted to establish its therapeutic potential and its mechanisms of action., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The use of psychostimulant drugs can modify brain function by inducing changes in the reward system, mainly due to alterations in dopaminergic and glutamatergic transmissions in the mesocorticolimbic pathway. However, the etiopathogenesis of addiction is a much more complex process. Previous data have suggested that microglia and other immune cells are involved in events associated with neuroplasticity and memory, which are phenomena that also occur in addiction. Nevertheless, how dependent is the development of addiction on the activity of these cells? Although the mechanisms are not known, some pathways may be involved. Recent data have shown psychoactive substances may act directly on immune cells, alter their functions and induce various inflammatory mediators that modulate synaptic activity. These could, in turn, be involved in the pathological alterations that occur in substance use disorder. Here, we extensively review the studies demonstrating how cocaine and amphetamines modulate microglial number, morphology, and function. We also describe the effect of these substances in the production of inflammatory mediators and a possible involvement of some molecular signaling pathways, such as the toll-like receptor 4. Although the literature in this field is scarce, this review compiles the knowledge on the neuroimmune axis that is involved in the pathogenesis of addiction, and suggests some pharmacological targets for the development of pharmacotherapy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The excessive consumption of ultra-processed foods and the development of obesity has been associated with several comorbidities, including psychiatric disorders. Excess fat tissue promotes a low-intensity inflammatory state, mainly in the white tissue, which is essential in developing metabolic alterations and influences brain homeostasis. In this scenario, Cannabidiol (CBD), a compound from Cannabis sativa, has presented anxiolytic and anti-inflammatory effects in murine models. This study verified whether CBD treatment would ameliorate the compulsive-like and anxiety-like behaviors observed after mice's chronic consumption of a high-refined carbohydrate (HC) diet. BALB/c male mice received a control or HC diet for 12 weeks followed by vehicle and CBD (30 mg/Kg, i.p.) administration, and their behavior was evaluated in the Marble Burying test (MB) and Novel Suppressing Feeding test (NSF). The sub-chronic, but not acute, treatment with CBD attenuated the compulsive-like and anxiogenic-like behavior induced by the HC diet. Our data reinforced the harmful effects of the HC diet's chronic consumption on compulsive and anxious behaviors and the potential of CBD as a drug treatment for psychiatric disorders associated with obesity., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The phytocannabinoid cannabidiol (CBD) has previously shown to have anticonvulsant effects in preclinical and clinical studies. Recently, CBD has been approved to treat certain types of drug-resistant epileptic syndromes. However, the underlying mechanism of action remains unclear. The phosphatidylinositol 3-kinase (PI3K) signaling pathway has been proposed to modulate seizures and might be recruited by CBD. Thus, we tested the hypothesis that the anticonvulsant effect of CBD involves PI3K in a seizure model induced by pentylenetetrazole (PTZ)., Methods: We employed pharmacological and genetic approaches to inhibit PI3K and quantified its effects on seizure duration, latency, and number., Results: PI3K genetic ablation increased the duration and number of seizures. CBD inhibited PTZ-induced seizures in mice. Genetic deletion of PI3K or pretreatment with the selective inhibitor LY294002 prevented CBD effects., Conclusion: Our data strengthen the hypothesis that the CBD anticonvulsant effect requires the PI3K signaling pathway., (© 2022. The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences.)

Cocaine-induced neuroinflammation plays an important role in the pathophysiology of drug addiction. Evidence suggests that the immune response contributes for memory consolidation related to place preference behavior underlying cocaine administration in mice. Conditioned place preference (CPP) is a protocol extensively used to study the rewarding and/or aversive motivational effects of drug abuse in rodents, reproducing cocaine-seeking behavior in humans. Besides the variety of apparatus used in the CPP protocol, whether different types of apparatus are able to induce the same conditioned behavior response and neurobiological changes remains to be fully explored. We hypothesize that the immune response is involved in the cocaine-induced CPP and that the type of apparatus might influence this response. Herein, two- and three-compartment apparatuses were tested using the behavioral model of CPP. Cocaine-induced CPP was demonstrated in both apparatuses. However, mice injected with cocaine had decreased levels of IL-1β, IL-6, IL-10, and GDNF in the pre-frontal cortex, and decreased CX3CL1 in the striatum, in the CPP protocol using three compartments compared to controls. While similar levels were seen in the CPP protocol using two compartments. In conclusion, the current study demonstrated that the type of apparatus might influence the investigation of neurobiological mechanisms associated with cocaine-induced CPP. Our data also suggest that the three compartment-apparatus seems to be a more appropriate model to investigate the neuroinflammatory response related to cocaine addiction., (Copyright © 2022. Published by Elsevier B.V.)

Colibacillosis is one of the most important diseases in poultry production. The use of antimicrobials remains a therapeutic cornerstone for avian pathogenic E. coli (APEC), thereby contributing to the development of antimicrobial resistance (AMR). The aim of this study was to characterize AMR in broiler breeder flocks reared under commercial conditions. Data covering 10 years, from 2009 to 2018, were used to evaluate the phenotypic AMR of 264 APEC isolates obtained from 158 broiler breeder flocks of a large company in Portugal. The APEC isolates were tested against eleven antimicrobials by the Kirby-Bauer disc diffusion test. The annual proportion of AMR was calculated by dividing the number of APEC isolates with phenotypic resistance by the total number of APEC isolated that year. Similarly, the overall AMR of the whole period was calculated. The relationship of antimicrobial resistance with time (years) was investigated with a generalized linear model using logistic regression. The overall AMR of the 10-year period was: amoxicillin 78%, ampicillin 73.5%, tetracycline 63.3%, doxycycline 56.4%, apramycin 34.5%, neomycin 68.2%, enrofloxacin 32.6%, flumequine 39.4%, co-trimoxazole 47.7%, florfenicol 46.6% and lincospectin 66.3%. Over time, a significant decrease in AMR was observed for amoxicillin and ampicillin, neomycin, flumequine, co-trimoxazole, florfenicol and lincospectin. Multidrug resistance (MDR) decreased from 100% in 2009 to 48% in 2018. Only seven (2.7%) APEC strains were fully susceptible to all tested antimicrobials. The decrease over time of AMR in APEC likely reflects the efficacy of manifold improvements in broiler breeder production systems. A further reduction in AMR is still desirable. RESEARCH HIGHLIGHTSDecreasing trend of antimicrobial resistance in avian pathogenic E. coli over time.Over 50% of isolates still resistant to amoxicillin, tetracycline and doxycycline.Multidrug resistance decreased from 100% in 2009 to 48% in 2018.Further reduction of antimicrobial resistance in broiler breeders desirable.

Background: There is a growing literature on the potential medical uses of Cannabis sativa and cannabinoid compounds. Although these have only been approved by regulatory agencies for a few indications, there is a hype about their possible benefits in a variety of conditions and a large market in the wellness industry. As in many cases patients search for information on cannabis products online, we have analyzed the information on medical cannabis available on the Internet. Therefore, this study aims at assessing the quality of the information available online on medical cannabis., Methods: We searched "medical cannabis" on June 2019 using google.com and downloaded the first 243 websites. After excluding dead links or websites with no information about cannabis, 176 websites were included. They were then classified for their typology (e.g., commercial, government, news outlets). As an indicator of trustworthiness, we used the Journal of American Medical Association (JAMA) score, which assesses the indication of date, author, ownership of the website, and the presence of references. We also considered if a website is certified by Health-On-the-Net (HON), an independent organization, by displaying a HONCode symbol. Subsequently, we performed a content analysis to assess both the medical cannabis indications mentioned by webpages and the completeness of the information provided (whether they mentioned potential side effects and legal/regulatory issues or not)., Results: Analyzing 176 webpages returned by a search engine, we found that 52% of them were news websites. Pain, epilepsy, and multiple sclerosis were the most frequently mentioned therapeutic areas (cited in 92, 84 and 80 webpages, respectively), which did not always match those for which there is regulatory approval. Information was also incomplete, with only 22% of the webpages mentioning potential side effects. Health portal websites provided the most complete information, with all of them (n = 7) reporting side effects. On average, 80% of webpages had a neutral stance on the potential benefits of medical cannabis, with commercial websites having more frequently a positive stance (67%)., Conclusions: We conclude that the information that can be found online is not always aligned in terms of the therapeutic areas for which science-based evidence is often still weak., (© 2022. The Author(s).)

Bckground: Aripiprazole is an antipsychotic drug used to treat schizophrenia and bipolar disorder. Recently, its peripheral analgesic component was evaluated, however, the mechanism involved in this effect is not fully established. Therefore, the aim of the study was to obtain pharmacological evidence for the involvement of the nitric oxide system in the peripheral antinociceptive effect induced by aripiprazole., Methods: The hyperalgesia was induced via intraplantar injection of prostaglandin E 2 in mice and the nociceptive thresholds were evaluated using the paw pressure test. All drugs were injected locally into the right hind paw., Results: The PI3K inhibitor (AS605240), but not rapamycin (mTOR kinase inhibitor), reversed the peripheral antinociceptive effect induced by Aripiprazole. Antinociception was antagonized by the non-selective inhibitor of the nitric oxide synthase (L-NOarg). The same response was observed using the selective iNOS, but not with the selective nNOS inhibitors. The selective guanylyl cyclase enzyme inhibitor (ODQ) and the non-selective potassium channel blocker tetraethylammonium were able to reverse the antinociceptive effect of aripiprazole. The same was seen using glibenclamide, an ATP-dependent K + channel blocker. However, calcium-activated potassium channel blockers of small and high conductance, dequalinium chloride and paxilline, respectively, did not reverse this effect. The injection of cGMP-specific phosphodiesterase type 5 inhibitor zaprinast, potentiated the antinociceptive effect induced by a low dose of aripiprazole., Conclusion: The results provide evidence that aripiprazole induces peripheral antinociceptive effects via PI3K/NO/cGMP/K ATP pathway activation., (© 2022 European Pain Federation - EFIC®.)

Drug abuse and addiction can be initiated and reinstated by contextual stimuli previously paired with the drug use. The influence exerted by the context on drug-seeking behaviour can be modelled in experimental animals with place-conditioning protocols. Here, we review the effects of cannabinoids in place conditioning and the therapeutic potential of the endocannabinoid system for interfering with drug-related memories. The phytocannabinoid Δ9-tetrahydrocannabinol (THC) tends to induce conditioned place preference (CPP) at low doses and conditioned place aversion at high doses; cannabidiol is devoid of any effect, yet it inhibits CPP induced by some drugs. Synthetic CB1 receptor agonists tend to recapitulate the biphasic profile observed with THC, whereas selective antagonists/inverse agonists inhibit CPP induced by cocaine, nicotine, alcohol and opioids. However, their therapeutic use is limited by potential psychiatric side effects. The CB2 receptor has also attracted attention, because selective CB2 receptor agonists inhibit cocaine-induced CPP. Inhibitors of endocannabinoid membrane transport and hydrolysis yield mixed results. In targeting the endocannabinoid system for developing new treatments for drug addiction, future research should focus on 'neutral' CB1 receptor antagonists and CB2 receptor agonists. Such compounds may offer a well-tolerated pharmacological profile and curb addiction by preventing drug-seeking triggered by conditioned contextual cues., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The endocannabinoid system modulates the stress coping strategies in the dorsolateral periaqueductal grey (dlPAG). The most relevant endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG) exert inhibitory control over defensive reactions mediated by the dlPAG. However, the protective role of anandamide is limited by its lack of effect in higher concentrations. Thus, the 2-AG emerges as a complementary target for developing new anxiolytic compounds. Nevertheless, the role of 2-AG on stress responsivity may vary according to the nature of the stimulus. In this study, we verified whether the dlPAG injection of 2-AG or inhibitors of its hydrolysis induce anxiolytic-like effects in male Wistar rats exposed to behavioral models in which physical stress (mild electric shock) is a critical component, namely the contextual fear conditioning test (CFC) and the Vogel conflict test (VCT). We also investigated the contribution of cannabinoid receptor type 1 (CB1) and type 2 (CB2) in such effects. The facilitation of 2-AG signaling in the dlPAG reduced contextual fear expression and exhibited an anxiolytic-like effect in the VCT in a mechanism dependent on activation of CB1 and CB2. However, the VCT required a higher dose than CFC. Further, the monoacylglycerol inhibitors, which inhibit the hydrolysis of 2-AG, were effective only in the CFC. In conclusion, we confirmed the anti-aversive properties of 2-AG in the dlPAG through CB1 and CB2 mechanisms. However, these effects could vary according to the type of stressor and the anxiety model employed., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The transient receptor potential vanilloid-1 channel (TRPV1) is responsible for decoding physical and chemical stimuli. TRPV1 is activated by capsaicin (a compound from chili peppers), heat (above 43°C) and acid environment, playing a major role in pain, inflammation and body temperature. Molecular and histological studies have suggested TRPV1 expression in specific brain regions, where it can be activated primarily by the endocannabinoid anandamide, fostering studies on its potential role in psychiatric disorders. TRPV1 blockers are effective in various animal models predictive of anxiolytic and antipanic activities, in addition to reducing conditioned fear. In models of antidepressant activity, these compounds reduce behavioral despair and promote active stress-coping behavior. TRPV1 blockers also reduce the effects of certain drugs of abuse and revert behavioral changes in animal models of neurodevelopmental disorders. The main limiting factor in developing TRPV1 blockers as therapeutic agents concerns their effects on body temperature, particularly hyperthermia. New compounds, which block specific states of the channel, could represent an alternative. Moreover, compounds blocking both TRPV1 and the anandamide-hydrolyzing enzyme, fatty acid amide hydrolase (FAAH), termed dual TRPV1/FAAH blockers, have been investigated with promising results. Overall, preclinical studies yield favorable results with TRPV1 blockers in animal models of psychiatric disorders., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Microglia play a major role in certain neuropathological conditions. In a recent paper, Reusch et al. demonstrated how signaling pathways downstream of cannabinoid type 2 (CB 2 ) and toll-like receptors (TLRs) converge in these cells. The findings suggest that CB 2 receptors play a permissive role in microglia activation mediated by TLRs., Competing Interests: Declaration of interests The authors declare no other competing interests in relation to this work., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Sustainability indicators have become essential tools to deal with compartmentalized resources planning and management in cities. The development of water, energy, and food nexus (WEF nexus) indicators is a prominent goal of current research, but the focus is mainly on economic issues and material flows. Attention to the local scale and context, social aspects, and the inclusion of non-academic actors is mostly lacking. To address these gaps, this paper reports and reflects on the co-creation of sustainability indicators related to the WEF nexus in the city of São Paulo, Brazil. With a transdisciplinary approach, non-academic actors were included in the different stages of the process using the Urban Living Lab methodology, to improve the usability of the produced indicators' set. The case of São Paulo concerned on-going actions in the peri-urban and rural areas of the city which seek to improve environmental protection by stimulating more sustainable forms of agriculture. Thirty-four indicators were developed through a sequence of interactive activities, such as workshops, meetings, and field trips. The presented process aims to strongly enhance usability by actively involving users from the start, connecting the nexus approach to previous knowledge and familiar frameworks, paying attention to the local scale and context, and to social aspects, and by anticipating future use in various ways., (© The Author(s), under exclusive licence to Springer Japan KK, part of Springer Nature 2022.)

Background: Major depressive disorder (MDD) affects millions of people worldwide. While the exact pathogenesis is yet to be elucidated, the role of neuro-immune signaling has recently emerged. Despite major advances in pharmacotherapy, antidepressant use is marred by limited efficacy and potential side effects. Cannabidiol (CBD), a phytocannabinoid, exerts antidepressant-like effects in experimental animals. This study investigated the impact of CBD on sickness behavior (SB), a measure of depressive-like response, and neuro-immune changes induced by lipopolysaccharides (LPS) in mice., Methods: Socially isolated rodents were administered with LPS to trigger SB. and treated with CBD or its vehicle. Animals were submitted to forced swimming test, to evaluate depressive-like behavior, and to open field test, to evaluate locomotory activity. Immediately after behavioral analyses, animals were euthanized and had their hypothalamus, prefrontal cortex and hippocampus dissected, to proceed neurotrophins and cytokines analyses. ELISA was used to detect IL-1β, BDNF and NGF; and cytometric beads array to measure IL-2, IL-4, IL-6, IFN-γ, TNF-α and IL-10 levels., Results: CBD effectively prevented SB-induced changes in the forced swim test without altering spontaneous locomotion. This phytocannabinoid also partially reversed LPS-evoked IL-6 increase in both the hypothalamus and hippocampus. In addition, CBD prevented endotoxin-induced increase in BDNF and NGF levels in the hippocampus of SB animals., Conclusions: Apparently, CBD prevents both behavioral and neuro-immunological changes associated with LPS-induced SB, which reinforces its potential use as an antidepressant which modulates neuroinflammation. This opens up potentially new therapeutic avenues in MDD., (© 2021. Maj Institute of Pharmacology Polish Academy of Sciences.)

The mechanisms involved in the maintenance of cigarette smoking and nicotine reward remain unclear. Immune response might play an important role in this context. Nicotine may induce both central and systemic inflammatory responses as well as changes in the regulation of brain-derived neurotrophic factor (BDNF). The conditioned place preference (CPP) is a method used for the evaluation of nicotine-induced reward, reproducing nicotine-seeking behavior in humans. So far, there are no studies investigating the relationship between neuroinflammation and nicotine-induced CPP. This study aimed to evaluate the levels of inflammatory mediators and neurotrophic factors in key areas of the central nervous system (CNS) of mice subject to nicotine-induced CPP. CPP was induced with an intraperitoneal administration of 0.5 mg/kg of nicotine in male Swiss mice, using an unbiased protocol. Control group received vehicle by the same route. The levels of cytokines, chemokines, and neurotrophic factors were measured using Enzyme-Linked Immunosorbent Assay (ELISA) in the brain after CPP test. As expected, nicotine induced place preference behavior. In parallel, we observed increased peripheral levels of IL-6 and IL-10 alongside increased hippocampal levels of NGF but decreased GDNF in mice treated with nicotine compared to controls. In the striatum, nicotine promoted decrease of IL-1ß, IL-10 and GDNF levels, while the levels of all the mediators were similar between groups in the pre-frontal cortex. Our results provide evidence on the role of cytokines and neurotrophic factors in nicotine-induced CPP in mice., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Different data suggest that microglia may participate in the drug addiction process as these cells respond to neurochemical changes induced by the administration of these substances. In order to study the role of microglia in drug abuse, Swiss mice aged 8-9 weeks were treated with the CSF1R inhibitor PLX3397 (40 mg/kg, p.o.) and submitted to behavioral sensitization or conditioned place preference (CPP) induced by cocaine (15 mg/kg, i.p.). Thereafter, brains were used to evaluate the effects of CSF1R inhibition and cocaine administration on morphological, biochemical and molecular changes. CSF1R inhibition attenuated behavioral sensitization, reduced the number of Iba-1 + cells and increased ramification and lengths of the branches in the remaining microglia. Additionally, both cocaine and PLX3397 increased the cell body to total cell size ratio of Iba-1 + cells, as well as CD68 + and GFAP + stained areas, suggesting an activated pattern of the glial cells. Besides, CSF1R inhibition increased CX3CL1 levels in the striatum, prefrontal cortex and hippocampus, as well as reduced CX3CR1 expression in the hippocampus. In this region, cocaine also reduced BDNF levels, an effect that was enhanced by CSF1R inhibition. In summary, our results suggest that microglia participate in the behavioral and molecular changes induced by cocaine. This study contributes to the understanding of the role of microglia in cocaine addiction., (© 2021. The Author(s).)

This review focuses on the possible roles of phytocannabinoids, synthetic cannabinoids, endocannabinoids, and "transient receptor potential cation channel, subfamily V, member 1" (TRPV1) channel blockers in epilepsy treatment. The phytocannabinoids are compounds produced by the herb Cannabis sativa, from which Δ 9 -tetrahydrocannabinol (Δ 9 -THC) is the main active compound. The therapeutic applications of Δ 9 -THC are limited, whereas cannabidiol (CBD), another phytocannabinoid, induces antiepileptic effects in experimental animals and in patients with refractory epilepsies. Synthetic CB 1 agonists induce mixed effects, which hamper their therapeutic applications. A more promising strategy focuses on compounds that increase the brain levels of anandamide, an endocannabinoid produced on-demand to counteract hyperexcitability. Thus, anandamide hydrolysis inhibitors might represent a future class of antiepileptic drugs. Finally, compounds that block the TRPV1 ("vanilloid") channel, a possible anandamide target in the brain, have also been investigated. In conclusion, the therapeutic use of phytocannabinoids (CBD) is already in practice, although its mechanisms of action remain unclear. Endocannabinoid and TRPV1 mechanisms warrant further basic studies to support their potential clinical applications. This article is part of the Special Issue "NEWroscience 2018"., Competing Interests: Declaration of competing interest The authors have no conflict of interest to report., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Tardive dyskinesia (TD) is a side effect associated with the long-term use of certain antipsychotics. Considering the modulatory role of the endocannabinoid system upon dopaminergic neurotransmission, the present study tested the hypothesis that increasing endocannabinoid (anandamide and 2-arachidonoylglycerol) levels attenuates haloperidol-induced TD (vacuous chewing movements, VCMs) in male Wistar rats. The animals received administration of chronic haloperidol (38 mg/kg; 29 days) followed by acute FAAH (URB597, 0.1-0.5 mg/kg) or MAGL (JZL184, 1-10 mg/kg) inhibitors before VCM quantification. The underlying mechanisms were evaluated by pre-treatments with a CB 1 receptor antagonist (AM251, 1 mg/kg) or a TRPV 1 channel blocker (SB366791, 1 mg/kg). Moreover, CB 1 receptor expression was evaluated in the striatum of high-VCM animals. As expected, haloperidol induced VCMs only in a subset of rats. Either FAAH or MAGL inhibition reduced VCMs. These effects were prevented by CB 1 receptor antagonism, but not by TRPV1 blockage. Remarkably, CB 1 receptor expression was increased high-VCM rats, with a positive correlation between the levels of CB 1 expression and the number of VCMs. In conclusion, increasing endocannabinoid levels results in CB 1 receptor-mediated protection against haloperidol-induced TD in rats. The increased CB 1 receptor expression after chronic haloperidol treatment suggests a counter-regulatory protective mechanism., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Cocaine addiction is a severe mental disorder for which few treatment options are available. The underlying mechanisms include facilitation of monoamine-neurotransmission, particularly dopamine. Here, we tested the hypothesis that the monoamine stabilizers, (-)-OSU6162 ((3S)-3-(3-methylsulfonylphenyl)-1-propylpiperidine) and aripiprazole (7-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]-3,4-dihydro-1H-quinolin-2-one), prevent cocaine-induced behaviors. Male Swiss mice received injections of (-)-OSU6162 or aripiprazole and cocaine and were tested for cocaine-induced hyperlocomotion, locomotor sensitization, and acquisition and expression of conditioned place preference (CPP). The increase in the distance traveled induced by cocaine (20 mg/kg) was prevented by pretreatment with aripiprazole (1 and 10 mg/kg), whereas (-)-OSU6162 (3 mg/kg) exerted a minor effect. Aripiprazole, however, also impaired spontaneous locomotion. Neither (-)-OSU6162 nor aripiprazole interfered with the locomotor sensitization and expression of CPP induced by cocaine (15 mg/kg). (-)-OSU6162 (3 mg/kg), but not aripiprazole, prevented the acquisition of CPP induced by cocaine (15 mg/kg). (-)-OSU6162 exerts a minor effect in reducing cocaine-induced stimulatory activity and context-related memories, which are responsible for triggering drug seeking. Further studies are required to establish whether (-)-OSU6162 could be a candidate drug for the treatment of cocaine addiction.

Objective: The present study was designed to test the hypothesis that there is a reduction in the activity of the enzyme cytochrome c oxidase (Cox) in Alzheimer's disease (AD)., Methods: Systematic review of literature and meta-analysis were used with data obtained from the PubMed, Scopus, MEDLINE, Lilacs, Eric and Cochrane. The keywords were Alzheimer's AND Cox AND mitochondria; Alzheimer's AND Cox AND mitochondria; Alzheimer's AND complex IV AND mitochondria. A total of 1372 articles were found, 23 of them fitting the inclusion criteria. The data were assembled in an Excel spreadsheet and analysed using the RevMan software. A random effects model was adopted to the estimative of the effect., Results: The data shows a significant decrease in the activity of the Cox AD patients and animal models., Conclusion: Cox enzyme may be an important molecular component involved in the mechanisms underlying AD. Therefore, this enzyme may represent a possible new biomarker for the disease as a complementary diagnosis and a new treatment target for AD.

Panic disorder can be categorized into the nonrespiratory or the respiratory subtypes, the latter comprising dyspnea, shortness of breath, chest pain, feelings of suffocation, and paresthesias. Doxapram is an analeptic capable of inducing panic attacks with respiratory symptoms in individuals diagnosed with the disorder; however, its neuroanatomical targets and its effects on experimental animals remain uncharacterized. One of the brain regions proposed to trigger panic attacks is the midbrain periaqueductal gray (PAG). Therefore, in this study, we evaluated the effects of doxapram in Fos (c-Fos) protein expression in the PAG and characterized its cardiorespiratory and behavioral effects on the elevated T maze and in the conditioned place aversion (CPA) paradigms. Doxapram increased Fos expression in different columns of the PAG, increased respiratory frequency, decreased heart rate, and increased arterial pressure when injected via intravenous route. Alprazolam, a panicolytic benzodiazepine, injected via intraperitoneal route, decreased respiratory frequency, whereas URB597, an anandamide hydrolysis inhibitor injected via intraperitoneal route, was ineffective. Doxapram injected via intraperitoneal route induced an anxiogenic-like effect in the elevated T-maze model; however, it failed to induce CPA. This study suggests that the cardiorespiratory and behavioral effects of doxapram in rodents serve as an experimental model that can provide insights into the neurobiology of panic attacks., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

The pyridobenzoxazepine compound, 5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]benzoxazepine (JL13), has been developed as a potential antipsychotic drug. We tested the hypothesis that JL13 is efficacious in both dopaminergic and glutamatergic animal models of schizophrenia. We investigated JL13 for its efficacy to prevent cocaine- and ketamine-induced hyperlocomotion and MK-801-induced deficits in prepulse inhibition (PPI) of the startle reflex. Male Swiss mice received injections of JL13 (0.1-10 mg/kg) and were tested in the open field for basal locomotion. In separate experiments, the animals received injections of JL13 (0.1-3 mg/kg) followed by cocaine (10 mg/kg), ketamine (60 mg/kg), or MK-801 (0.5 mg/kg) and were tested in the open field for hyperlocomotion. In addition, it was also tested if JL13 prevented MK-801-induced disruption of PPI. Only the highest dose of JL13 impaired spontaneous locomotion, suggesting its favorable profile regarding motor side effects. At doses that did not impair basal motor activity, JL13 prevented cocaine-, ketamine-, and MK-801-induced hyperlocomotion. Moreover, JL13 prevented MK-801-induced disruption of PPI. Extending previous findings, this study shows that JL13 exerts antipsychotic-like activity in both dopaminergic and glutamatergic models. This compound has a favorable pharmacological profile, similar to second-generation antipsychotics., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Acute chagasic encephalitis is a clinically severe central nervous system (CNS) manifestation. However, the knowledge of the nervous form of Chagas disease is incomplete. The role of the muscarinic acetylcholine receptor (mAChR) on mice behavior and brain lesions induced by Trypanosoma cruzi (Colombian strain) was herein investigated in mice treated with the mAChR agonist and antagonist (carbachol and atropine), respectively. Immunosuppressed or non-immunosuppressed mice were intracerebroventricularly (icv) or intraperitoneally (ip) infected. All groups were evaluated 15 d.p.i. (days post infection). Intraperitoneally infected animals had subpatent parasitemia. Patent parasitemia occurred only in icv infected mice. The blockade of mAChR increased the parasitemia, parasitism and lesions compared to its activation. Infected not treated (INT ip) mice did not present meningitis and encephalitis, regardless of immunosuppression. INT icv brains presented higher cellularity, discrete signs of cellular degeneration, frequent presence of parasites and focal meningitis. The immunosuppressed atropine + icv mice presented increased intracellular parasitism associated with degenerative parenchymal changes, while carbachol + icv mice presented discrete meningitis, preservation of the cortex and absence of relevant parasitism. Cholinergic receptor blockage increased impairment of coordination vs. receptor activation. Muscarinic cholinergic pathway seems to be involved in immune mediated cell invasion events while its blockade favored infection evolution, brain lesions, and behavioral alterations.

The understanding that hyper-excitability and hyper-synchronism in epilepsy are indissociably bound by a cause-consequence relation has only recently been challenged. Thus, therapeutic strategies for seizure suppression have often aimed at inhibiting excitatory circuits and/or activating inhibitory ones. However, new approaches that aim to desynchronize networks or compromise abnormal coupling between adjacent neural circuitry have been proven effective, even at the cost of enhancing local neuronal activation. Although most of these novel perspectives targeting circuitry desynchronization and network coupling have been implemented by non-pharmacological devices, we argue that there may be endogenous neurochemical systems that act primarily in the desynchronization component of network behavior rather than dampening excitability of individual neurons. This review explores the endocannabinoid system as one such possible pharmacological landmark for mimicking a form of "on-demand" desynchronization analogous to those proposed by deep brain stimulation in the treatment of epilepsy. This essay discusses the evidence supporting the role of the endocannabinoid system in modulating the synchronization and/or coupling of distinct local neural circuitry; which presents obvious implications on the physiological setting of proper sensory-motor integration. Accordingly, the process of ictogenesis involves pathological circuit coupling that could be avoided, or at least have its spread throughout the containment of other areas, if such endogenous mechanisms of control could be activated or potentiated by pharmacological intervention. In addition, we will discuss evidence that supports not only a weaker role played on neuronal excitability but the potential of the endocannabinoid system strengthening its modulatory effect, only when circuitry coupling surpasses a level of activation., (Copyright © 2020 Medeiros, Cota, Oliveira, Moreira and Moraes.)

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/Akt)/mechanistic target of rapamycin (mTOR) signaling pathway has been associated with several pathologies in the central nervous system (CNS), including epilepsy. There is evidence supporting the hypothesis that the PI3Kγ signaling pathway may mediate the powerful anticonvulsant properties associated with the cannabinoidergic system. This work aims to investigate if the anticonvulsant and neuroprotective effects of cannabidiol (CBD) are mediated by PI3Kγ. In vitro and in vivo experiments were performed on C57Bl/6 wild-type (WT) and PI3Kγ - /- mice. Behavioral seizures were induced by bilateral intra-hippocampal pilocarpine microinjection. Twenty-four hours after the first behavioral seizure, animals were perfused and their brains removed and processed, for histological analysis of neurodegeneration, microgliosis and astrocytosis. Primary cultures of hippocampal neurons were used for glutamate-induced cell death assay. CDB increased latency and reduced the severity of pilocarpine-induced behavioral seizures, as well as prevented postictal changes, such as neurodegeneration, microgliosis and astrocytosis, in WT animals, but not in PI3Kγ -/- . CBD in vivo effects were abolished by pharmacological inhibition of cannabinoid receptor or mTOR. In vitro, PI3Kγ inhibition or deficiency also changed CBD protection observed in glutamate-induced cell death assay. Thus, we suggest that the modulation of PI3K/mTOR signaling pathway is involved in the anticonvulsant and neuroprotective effects of CBD. These findings are important not only for the elucidation of the mechanisms of action of CBD, which are currently poorly understood, but also to allow the prediction of therapeutic and side effects, ensuring efficacy and safety in the treatment of patients with epilepsy., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The basolateral amygdala (BLA) is critical in the control of the sympathetic output during stress. Studies demonstrated the involvement of the renin-angiotensin system components in the BLA. Angiotensin-(1-7) [Ang-(1-7)], acting through Mas receptors, reduces stress effects. Considering that angiotensin-converting enzyme 2 (ACE2) is the principal enzyme for the production of Ang-(1-7), here we evaluate the cardiovascular reactivity to acute stress after administration of the ACE2 activator, diminazene aceturate (DIZE) into the BLA. We also tested whether systemic treatment with DIZE could modify synaptic activity in the BLA and its effect directly on the expression of the N-methyl-d-aspartate receptors (NMDARs) in NG108 neurons in-vitro. Administration of DIZE into the BLA (200 pmol/100 nL) attenuated the tachycardia to stress (ΔHR, bpm: vehicle = 103 ± 17 vs DIZE = 49 ± 7 p = 0.018); this effect was inhibited by Ang-(1-7) antagonist, A-779 (ΔHR, bpm: DIZE = 49 ± 7 vs A-779 + DIZE = 100 ± 15 p = 0.04). Systemic treatment with DIZE attenuated the excitatory synaptic activity in the BLA (Frequency (Hz): vehicle = 2.9 ± 0.4 vs. DIZE =1.8 ± 0.3 p < 0.04). NG108 cells treated with DIZE demonstrated decreased expression of l subunit NMDAR-NR1 (NR1 expression (a.u): control = 0.534 ± 0.0593 vs. DIZE = 0.254 ± 0.0260) of NMDAR and increases of Mas receptors expression. These data demonstrate that DIZE attenuates the tachycardia evoked by acute stress. This effect results from a central action in the BLA involving activation of Mas receptors. The ACE2 activation via DIZE treatment attenuated the frequency of excitatory synaptic activity in the basolateral amygdala and this effect can be related with the decreases of the NMDAR-NR1 receptor expression., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: to understand spirituality and religiosity in the experience of suffering, guilt, and death of the elderly with cancer., Method: qualitative research based on Viktor Frankl's Existential Analysis. Twenty phenomenological interviews were conducted with people over 60 years old undergoing chemotherapy treatment at an oncology unit of a hospital in the city of Salvador, Bahia State, Brazil, between August and October 2018., Results: the following categories emerged: Experiences spirituality and religiosity in the face of the tragic triad and existential emptiness; Uses spirituality/religiosity as resilience strategies. After apprehension of ontic aspects, it was possible the ontological understanding of spirituality and religiosity in the face of suffering, guilt, and death experienced in the elderly with cancer's daily life., Final Considerations: spirituality and religiosity were understood as coping strategies used in the unstable experience of the elderly with cancer, providing comfort and resilience.