Genetic ablation of the isoform γ of PI3K decreases antidepressant efficacy of ketamine in male mice.

About one-third of major depressive disorder (MDD) patients demonstrate unresponsiveness to classic antidepressants, and even the clinical efficacy of fast-acting drugs such as ketamine varies significantly among patients with treatment-resistant depression. Nevertheless, the lack of suitable animal models that mimic a possible ketamine-resistant phenotype challenges the understanding of resistance to drug treatment. In this study, we showed that PI3Kγ knock-out (KO) mice do not respond to classical doses of ketamine and classical antidepressants. PI3Kγ KO mice were unresponsive to both the rapid and sustained antidepressant-like effects of a single dose of ketamine in the forced swimming test. Additionally, they were unresponsive to the antidepressant-like effects induced by the tricyclic antidepressant imipramine and the selective serotonin reuptake inhibitor fluoxetine. However, acute pharmacological inhibition of PI3Kγ did not block the antidepressant-like effect of ketamine, showing that a chronic deficiency of the PI3Kγ-mediated pathway is necessary for the effects of classic doses of ketamine and antidepressants. Therefore, we propose that PI3Kγ participates in the antidepressant activity and is likely implicated in the neurobiology and phenotype observed in patients with MDD who demonstrate treatment resistance.

Lack of Acute Agomelatine Effect in a Model of Social Anxiety in Healthy Volunteers: A Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Agomelatine is an antidepressant drug that acts as an agonist of melatoninergic MT1/2 receptors and an antagonist of serotonergic 5-HT2C receptors. Studies suggest that agomelatine has anxiolytic properties in social anxiety, but there are no studies that assessed the effects of this compound in human experimental anxiety induced by a public speaking test. The objective of our investigation was to assess the effects of agomelatine on human experimental anxiety using the Simulation Public Speaking Test (SPST). METHODS: Agomelatine (25 mg, n = 14), citalopram (20 mg, n = 14), venlafaxine (75 mg, n = 14), or placebo (n = 14) were administered in single doses to healthy volunteers in a double-blind study. Subjective anxiety was assessed with the Visual Analogue Mood Scale. Arterial blood pressure, heart rate, and blood levels of prolactin and cortisol were also recorded, as well as plasma levels of the 3 drugs. RESULTS: The SPST induced significant subjective, physiological, and hormonal effects in all groups. The SPST also increased the anxiety and decreased mental sedation Visual Analogue Mood Scale factors during the anticipatory and performance phases of the test. Citalopram increased anxiety during the test in females, whereas agomelatine and venlafaxine were not different from placebo. CONCLUSIONS: Confirming previous results, a serotonin selective reuptake inhibitor, citalopram, caused an anxiogenic effect in the SPST only in females. Acute administration of a low dose of agomelatine failed to modify the behavioral and physiological changes caused by this test. Future studies using higher doses and repeated administration should investigate if agomelatine behavioral and physiological effects could be detected in human experimental anxiety models.

Cannabidiol modulates hippocampal genes involved in mitochondrial function, ribosome biogenesis, synapse organization, and chromatin modifications.

BACKGROUND: Cannabidiol (CBD) is one of the main cannabinoids present in Cannabis sativa female flowers. Previous investigation has already provided insights into the CBD molecular mechanism; however, there is no transcriptome data for CBD effects on hippocampal subfields. Here, we investigate transcriptomic changes in dorsal and ventral CA1 of adult mice hippocampus after 100 mg/kg of CBD administration (i.p.) for one or seven consecutive days. METHODS: C57BL/6JUnib mice were treated with either vehicle or CBD for 1 or 7 days. The collected brains were sectioned, and the hippocampal sub-regions were laser microdissected for RNA-Seq analysis. RESULTS: The transcriptome analysis following 7 days of CBD administration indicates the differential expression of 1559 genes in dCA1 and 2924 genes in vCA1. Furthermore, GO/KEGG analysis identified 88 significantly enriched biological process and 26 significantly enriched pathways for dCBD7, whereas vCBD7 revealed 128 enriched BPs and 24 pathways. CONCLUSION: This dataset indicates a widespread decrease of electron transport chain and ribosome biogenesis transcripts in CA1, while chromatin modifications and synapse organization transcripts were increased following CBD administration for 7 days.

Ayahuasca-enhanced extinction of fear behaviour: Role of infralimbic cortex 5-HT2A and 5-HT1A receptors.

BACKGROUND AND PURPOSE: Ayahuasca (AYA) is a botanical psychedelic with promising results in observational and small clinical trials for depression, trauma and drug use disorders. Its psychoactive effects primarily stem from N,N-dimethyltryptamine (DMT). However, there is a lack of research on how and where AYA acts in the brain. This study addressed these questions by examining the extinction of aversive memories in AYA-treated rats. EXPERIMENTAL APPROACH: We focused on the 5-HT1A and 5-HT2A receptors, as DMT exhibits a high affinity for both of them, along with the infralimbic cortex in which activity and plasticity play crucial roles in regulating the mnemonic process under analysis. KEY RESULTS: A single oral treatment with AYA containing 0.3 mg·kg-1 of DMT increased the within-session extinction of contextual freezing behaviour without affecting its recall. This protocol, when repeated twice on consecutive days, enhanced extinction recall. These effects were consistent for both 1- and 21-day-old memories in males and females. AYA effects on fear extinction were independent of changes in anxiety and general exploratory activity: AYA- and vehicle-treated animals showed no differences when tested in the elevated plus-maze. The 5-HT2A receptor antagonist MDL-11,939 and the 5-HT1A receptor antagonist WAY-100635 infused into the infralimbic cortex respectively blocked within- and between-session fear extinction effects resulting from repeated oral administration of AYA. CONCLUSION AND IMPLICATIONS: Our findings highlight complementary mechanisms by which AYA facilitates the behavioural suppression of aversive memories in the rat infralimbic cortex. These results suggest potential beneficial effects of AYA or DMT in stress-related disorders.

Long-term effects of ayahuasca in patients with recurrent depression: a 5-year qualitative follow-up

Background Ayahuasca is a botanical hallucinogenic preparation traditionally used by indigenous populations of Northwestern Amazonian countries for ritual and therapeutic purposes. It is rich in β-carboline alkaloids and N,N-dimethyltryptamine (DMT). Preclinical, observational, and experimental studies suggest that ayahuasca and its alkaloids have anxiolytic and antidepressive effects. We recently reported in an open-label trial that ayahuasca administration was associated with significant decreases in depression symptoms for 2-3 weeks after the experimental session in 17 patients with treatment-resistant major depressive disorder. Objectives To investigate if the experiment had any long-lasting effects on patients Methods Eight patients were interviewed 4 to 7 years after ayahuasca intake. Results Our results suggest that ayahuasca was well tolerated and that symptom reductions were limited to a few weeks. Importantly, most patients believed that the experience was among the most important of their lives, even 4-7 years later. Discussion To the best of our knowledge, this is the first long-term follow-up of a clinical sample that participated in an ayahuasca trial. Further studies with different and repeated dosing should be designed to further explore the antidepressive and anxiolytic effects of ayahuasca.

Effects of sodium nitroprusside in the prevention of schizophrenia-like symptoms induced by ketamine - A translational double-blind study

Abstract Background: Recent evidence has shown improvements in schizophrenia symptoms after the infusion of sodium nitroprusside (SNP), a nitric oxide (NO) donor. In the rat model of schizophrenia using ketamine injection, pretreatment with SNP seems to prevent behavioral changes associated with positive symptoms for up to one week. Objective: We investigated whether SNP would have preventative effects on psychogenic symptoms induced by ketamine in healthy subjects. Methods: Healthy subjects (N = 38) were assigned to distinct groups that received SNP in different doses (0.15, 0.25, and 0.5 mcg/kg/min). First, participants received an infusion of SNP or placebo over 75 minutes. After 10 minutes, they were injected for 1 minute with a bolus of 0.26 mg/kg of ketamine and a maintenance dose was started 5 minutes later, with 0.25 mg/kg/h of ketamine for 50 minutes. Results: Ketamine-induced psychopathological alterations induced were reduced by SNP, as assessed with the Brief Psychological Rating Scale. Scores in the objective subscale of the Clinician-Administered Dissociative States Scale were also lower in SNP sessions compared to placebo. SNP had protective effects against deterioration in facial emotion and identity recognition tasks induced by ketamine. Discussion: Our findings support the view that SNP has preventative properties against psychotic manifestations.

Arterial spin labeling in patients with schizophrenia: a systematic review

Abstract Background: Neuroimaging studies are an invaluable source of information about the physiopathology of schizophrenia. Arterial spin labeling (ASL) is a new magnetic resonance technique (MRI) that is able to effectively evaluate brain function without the use of radiation. Objective: To make a systematic review of studies using ASL to compare resting-state regional cerebral blood flow (rCBF) patterns in patients with schizophrenia and healthy controls. Methods: Original articles were searched for on PubMed, Scopus, Web of Science and PsycINFO electronic databases. The search terms used were 'arterial', 'spin', 'labeling', and 'schizophrenia'. Only studies comparing resting-state rCBF were included, a qualitative synthesis was then performed. Results: Ten articles were included in the review among a total of 22. Decreased rCBF in schizophrenia patients was described in the anterior cingulate, cuneus, fusiform gyrus, frontal lobe, left middle frontal gyrus, inferior frontal gyrus, lingual gyrus, middle occipital gyrus, and parietal lobe. The putamen was the only region with increased rCBF in schizophrenia. Discussion: The evidence of the studies reviewed lends support to the concept of hipofrontality in schizophrenia. rCBF alterations were found in regions classically associated with schizophrenia. ASL seems to be valid, and reliable tool to assess schizophrenia.

Antidepressive and anxiolytic effects of ayahuasca: a systematic literature review of animal and human studies

Objective: To conduct a systematic literature review of animal and human studies reporting anxiolytic or antidepressive effects of ayahuasca or some of its isolated alkaloids (dimethyltryptamine, harmine, tetrahydroharmine, and harmaline). Methods: Papers published until 3 April 2015 were retrieved from the PubMed, LILACS and SciELO databases following a comprehensive search strategy and using a predetermined set of criteria for article selection. Results: Five hundred and fourteen studies were identified, of which 21 met the established criteria. Studies in animals have shown anxiolytic and antidepressive effects of ayahuasca, harmine, and harmaline, and experimental studies in humans and mental health assessments of experienced ayahuasca consumers also suggest that ayahuasca is associated with reductions in anxiety and depressive symptoms. A pilot study reported rapid antidepressive effects of a single ayahuasca dose in six patients with recurrent depression. Conclusion: Considering the need for new drugs that produce fewer adverse effects and are more effective in reducing anxiety and depression symptomatology, the described effects of ayahuasca and its alkaloids should be further investigated.

Acute and chronic administration of cannabidiol increases mitochondrial complex and creatine kinase activity in the rat brain

Objective: To investigate the effects of cannabidiol (CBD) on mitochondrial complex and creatine kinase (CK) activity in the rat brain using spectrophotometry. Method: Male adult Wistar rats were given intraperitoneal injections of vehicle or CBD (15, 30, or 60 mg/kg) in an acute (single dose) or chronic (once daily for 14 consecutive days) regimen. The activities of mitochondrial complexes and CK were measured in the hippocampus, striatum, and prefrontal cortex. Results: Both acute and chronic injection of CBD increased the activity of the mitochondrial complexes (I, II, II-III, and IV) and CK in the rat brain. Conclusions: Considering that metabolism impairment is certainly involved in the pathophysiology of mood disorders, the modulation of energy metabolism (e.g., by increased mitochondrial complex and CK activity) by CBD could be an important mechanism implicated in the action of CBD. .

Quality of life in patients with Charcot-Marie-Tooth disease type 1A / Análise da qualidade de vida de pacientes com a doença de Charcot-Marie-Tooth tipo 1A

We assessed the functional impairment in Charcot-Marie-Tooth resulting from 17p11.2-p12 duplication (CMT1A) patients using the Short-Form Health Survey (SF-36), which is a quality of life questionnaire. Twenty-five patients of both genders aged ≥10 years with a positive molecular diagnosis of CMT1A were selected. Age- and gender-matched Control Group (without family history of neuropathy), and the sociodemographic and professional conditions similar to the patients' group were selected to compare the SF-36 results between them. The results showed that the majority quality of life impairments in CMT1A patients occurred in the social and emotional domains. Functional capacity also tended to be significantly affected; other indicators of physical impairment were preserved. In conclusion, social and emotional aspects are mostly neglected in the assistance provided to CMT1A Brazilian patients, and they should be better understood in order to offer global health assistance with adequate quality of life as a result.

Avaliou-se o comprometimento funcional de pacientes com Charcot-Marie-Tooth provenientes da duplicação 17p11.2-p12 (CMT1A), utilizando o SF-36, que é um questionário para medir a qualidade de vida. Vinte e cinco pacientes de ambos os sexos com idades ≥10 anos e diagnóstico molecular de CMT1A foram selecionados. Idade, sexo, condições sociodemográficas e profissionais foram pareados com o Grupo Controle (sem histórico familiar de neuropatia). Os resultados mostraram que o maior impacto da CMT1A na qualidade de vida ocorreu nos domínios social e emocional dos pacientes avaliados. A capacidade funcional também tende a ser significativamente afetada, enquanto outros indicadores de deficiência física foram preservados. Por fim, os aspectos sociais e emocionais dos pacientes acometidos por CMT1A costumam ser negligenciados na assistência médica prestada aos pacientes brasileiros, e devem ser melhor compreendidos a fim de oferecer uma assistência global à saúde, resultando em adequada qualidade de vida.

Nitric oxide plasma/serum levels in patients with schizophrenia: a systematic review and meta-analysis / Níveis plasmáticos/séricos do óxido nítrico em pacientes com esquizofrenia: uma revisão sistemática e metanálise

For the last 40 years, schizophrenia has been considered to be the result primarily of a dysfunction in brain dopaminergic pathways. In this review, it is described and discussed findings concerning nitric oxide-mediated neurotransmission in schizophrenia. Studies were searched in PubMed, SciELO, and LILACS using the terms schizophrenia and nitric oxide plasma levels or nitric oxide serum levels, with no time limit. The reference lists of selected articles were also hand-searched for additional articles. From 15 potential reports, 10 were eligible to be included in the review and meta-analysis. These studies included a total of 505 patients with schizophrenia and 339 healthy volunteers. No significant difference was found between patients and healthy controls regarding total nitrite plasma/serum levels (effect size g = 0.285, 95%CI = -0.205 to 0.774, p = 0.254). However, when studies with patients under antipsychotic treatment were examined separately, there was a significant difference between patients and healthy volunteers (effect size g = 0.663, 95%CI = 0.365 to 0.961, p < 0.001), showing that patients under treatment have higher levels of plasma/serum nitric oxide than controls. These results suggest that antipsychotics increase nitric oxide plasma/serum levels and that the nitrergic pathway would be a fertile target for the development of new treatments for patients with schizophrenia.

Durante os últimos 40 anos, a esquizofrenia foi considerada, principalmente, como o resultado de disfunções dopaminérgicas no cérebro. Esta revisão descreve e discute algumas descobertas sobre a neurotransmissão mediada pelo óxido nítrico na esquizofrenia. A busca foi feita nas bases PubMed, SciELO e LILACS usando-se os termos schizophrenia e nitric oxide plasma levels ou nitric oxide serum levels, sem limites de tempo. As listas de referências dos artigos selecionados foram examinadas em busca de outras publicações pertinentes. Dentre 15 artigos passíveis de serem incluídos, 10 preenchiam os critérios estabelecidos para a revisão e metanálise. Esses estudos incluíram 505 pacientes com esquizofrenia e 339 voluntários saudáveis. Não foram encontradas diferenças significativas entre pacientes e voluntários saudáveis quanto aos níveis plasmáticos de nitrito total (effect size g = 0,285, IC 95% = -0,205 a 0,774, p = 0,254). No entanto, o exame separado dos estudos envolvendo pacientes em tratamento antipsicótico apresentou diferenças significativas entre pacientes e voluntários saudáveis (effect size g = 0,663, IC 95% = 0,365 to 0,961, p < 0,001), demonstrando que pacientes em tratamento possuem níveis plasmáticos mais altos de óxido nítrico. Esses resultados sugerem que os antipsicóticos podem aumentar os níveis plasmáticos de óxido nítrico e que a via nitrérgica (e sua estimulação) constituiria um alvo propício para o desenvolvimento de novos tratamentos para pacientes com esquizofrenia.

Neuroimaging in specific phobia disorder: a systematic review of the literature / Neuroimagem do transtorno de fobia específica: uma revisão sistemática da literatura

OBJECTIVE: Specific phobia (SP) is characterized by irrational fear associated with avoidance of specific stimuli. In recent years, neuroimaging techniques have been used in an attempt to better understand the neurobiology of anxiety disorders. The objective of this study was to perform a systematic review of articles that used neuroimaging techniques to study SP. METHOD:A literature search was conducted through electronic databases, using the keywords: imaging, neuroimaging, PET, spectroscopy, functional magnetic resonance, structural magnetic resonance, SPECT, MRI, DTI, and tractography, combined with simple phobia and specific phobia. One-hundred fifteen articles were found, of which 38 were selected for the present review. From these, 24 used fMRI, 11 used PET, 1 used SPECT, 2 used structural MRI, and none used spectroscopy. RESULT: The search showed that studies in this area were published recently and that the neuroanatomic substrate of SP has not yet been consolidated. CONCLUSION: In spite of methodological differences among studies, results converge to a greater activation in the insula, anterior cingulate cortex, amygdala, and prefrontal and orbitofrontal cortex of patients exposed to phobia-related situations compared to controls. These findings support the hypotheses of the hyperactivation of a neuroanatomic structural network involved in SP.

A Fobia Específica (SP do inglês) é caracterizada por medos irracionais associados à evitação de estímulos específicos. Nos últimos anos, técnicas de neuroimagem vêm sendo empregadas na tentativa de melhor compreender a neurobiologia dos transtornos de ansiedade. O objetivo do presente estudo é realizar uma revisão sistemática dos artigos que utilizaram neuroimagem para estudar a SP. A busca na literatura foi realizada por intermédio de indexadores eletrônicos, utilizando-se as palavras-chave: imaging, neuroimaging, PET, spectroscopy, functional magnetic ressonance, structural magnetic ressonance, SPECT, MRI, DTI e tractography, cruzadas individualmente com os termos simple phobia e specific phobia. Foram encontrados 115 artigos, sendo 38 deles selecionados para a presente revisão. Desses, 24 usaram fMRI, 11 usaram PET, 1 usou SPECT, 2 usaram MRI estrutural e nenhum artigo de espectroscopia. Verifica-se que os estudos na área foram publicados recentemente e que, até o momento, o substrato neuroanatômico deste transtorno não está consolidado. Apesar das diferenças metodológicas entre os estudos, os resultados convergem para maior ativação na ínsula, cíngulo anterior, amídala e córtex préfrontal e orbitofrontal dos pacientes expostos a situações phobia related quando comparados aos controles. Esses achados reforçam hipóteses a respeito da hiperativação de uma determinada rede de estruturas neuroanatômicas envolvidas no transtorno de SP.