Cannabidiol modulates contextual fear memory consolidation in animals with experimentally induced type-1 diabetes mellitus.

OBJECTIVES: In view of the neuroprotective characteristic of cannabidiol (CBD) and its beneficial action on aversive memory in non-diabetic animals, we aimed to investigate in animals with experimentally induced type-1 diabetes mellitus (T1DM) whether CBD treatment would be able to impair the contextual fear memory consolidation, its generalisation and whether the effect would be lasting. We also investigated the CBD effect on anxiety-like responses. METHODS: After T1DM induction, animals received single or more prolonged treatment with CBD and were submitted to the contextual fear conditioning test. As expression of activity-regulated cytoskeletal-associated (Arc) protein is necessary for memory consolidation, we evaluated its expression in the dorsal hippocampus (DH). For evaluating anxiety-related responses, animals were submitted to the elevated plus maze test (EPMT), in which the time and number of entries in the open arms were used as anxiety index. RESULTS: A single injection of CBD impaired the contextual fear memory consolidation and its generalisation, which was evaluated by exposing the animal in a neutral context. This single injection was able to reduce the elevated expression of Arc in the DH from these animals. Interestingly, more prolonged treatment with CBD also impaired the persistence of context-conditioned fear memory and induced an anxiolytic-like effect, as the treated group spent more time in the open arms of the EPMT. CONCLUSION: CBD interferes with contextual fear memory and the dosage regimen of treatment seems to be important. Moreover, we cannot rule out the involvement of emotional aspects in these processes related to fear memory.

Simultaneous determination of amino acids and neurotransmitters in plasma samples from schizophrenic patients by hydrophilic interaction liquid chromatography with tandem mass spectrometry.

A sensitive, reproducible, and rapid method was developed for the simultaneous determination of underivatized amino acids (aspartate, serine, glycine, alanine, methionine, leucine, tyrosine, and tryptophan) and neurotransmitters (glutamate and γ-aminobutyric acid) in plasma samples using hydrophilic interaction liquid chromatography coupled to triple quadrupole tandem mass spectrometry. The plasma concentrations of amino acids and neurotransmitters obtained from 35 schizophrenic patients in treatment with clozapine (27 patients) and olanzapine (eight patients) were compared with those obtained from 38 healthy volunteers to monitor the effectiveness of treatment. The chromatographic conditions separated ten target compounds within 3 min. This method presented linear ranges that varied from (lower limit of quantification: 9.7-13.3 nmol/mL) to (upper limit of quantification: 19.4-800 nmol/mL), intra- and interassay precision with coefficients of variation lower than 10%, and relative standard error values of the accuracy ranged from -2.1 to 9.9%. The proposed method appropriately determines amino acids and neurotransmitters in plasma from schizophrenic patients. Compared with the control group (healthy volunteers), the plasma levels of methionine in schizophrenic patients treated with olanzapine are statistically significantly higher. Moreover, schizophrenic patients treated with clozapine tend to have increased plasma levels of glutamate.

Mental health trajectories of Brazilian health workers during two waves of the COVID-19 pandemic (2020-2021).

This study aimed to: (a) monitor the progression of symptoms of mental health burden among frontline workers caring for COVID-19 patients in Brazil during the two waves of the pandemic, considering the number of new cases and deaths, and; (b) to verify the different mental health outcomes and potential associations with current burnout symptoms. A non-probabilistic sample of health professionals was assessed as the pandemic progressed in Brazil (May/2020 August/2021). Standardized instruments focusing on anxiety, depression, insomnia, post-traumatic stress, and burnout symptoms were applied online. The results indicate a decrease in anxiety levels, what was related to when the number of new cases declined (end 1th-wave); symptoms returned to higher levels later. Emotional exhaustion increased when there was a higher incidence of cases, returning to the baseline levels at the end of the second wave. Depersonalization symptoms increased in this phase, characterized by a further decrease in new cases, while professional accomplishment decreased during the follow-up. The highest number of new cases was associated with a higher frequency of anxiety (OR = 1.467;95%CI = 1.109-1.941; p = 0.007) and professional accomplishment (OR = 1.490;95%CI = 1.098-2.023; p = 0.011). The subjects with trajectory of resilience against anxiety presented the lowest level of emotional exhaustion and depersonalization (p < 0.05). The conclusion is that the pressure experienced by healthcare professionals throughout the pandemic caused different impacts on their mental health, emphasizing the dynamic nature of this condition and the need for constant monitoring and care. This finding directly affects mental health prevention and intervention measures, which remain a priority and require continuous reinforcement, especially among the most vulnerable groups.

Two-weeks treatment with cannabidiol improves biophysical and behavioral deficits associated with experimental type-1 diabetes.

The prevalence rates of depression and anxiety are at least two times higher in diabetic patients, increasing morbidity and mortality. Cannabidiol (CBD) has been identified as a therapeutic agent viable to treat diverse psychiatric disorders. Thus, this study aimed to investigate the effect of CBD treatment (once a day for 14 days starting two weeks after diabetes induction; at doses of 0, 3, 10 or 30 mg/kg, i.p.) on depression- and anxiety-like behaviors associated with experimental diabetes induced by streptozotocin (60 mg/kg; i.p.) in rats. Levels of plasma insulin, blood glucose, and weight gain were evaluated in all experimental groups, including a positive control group treated with imipramine. The rats were tested in the modified forced swimming test (mFST) and elevated plus maze (EPM) test. Besides, the levels of serotonin (5-HT), noradrenaline (NA) and dopamine (DA) in two emotion-related brain regions, the prefrontal cortex (PFC) and hippocampus (HIP) were evaluated using high-pressure liquid chromatography. Our results showed that CBD treatment (only at the higher dose of 30 mg/kg) reduced the exaggerated depressive- and anxiogenic-like behaviors of diabetic (DBT) rats, which may be associated with altered 5-HT, NA and/or DA levels observed in the PFC and HIP. Treatment with CBD (higher dose) also induced a significant increase in weight gain and the insulin levels (and consequently reduced glycemia) in DBT rats. The long-term CBD effects gave rise to novel therapeutic strategies to limit the physiological and neurobehavioral deficits in DBT rats. This approach provided evidence that CBD can be useful for treating psychiatry comorbidities in diabetic patients.

Cannabidiol-induced panicolytic-like effects and fear-induced antinociception impairment: the role of the CB1 receptor in the ventromedial hypothalamus.

RATIONALE: The behavioural effects elicited by chemical constituents of Cannabis sativa, such as cannabidiol (CBD), on the ventromedial hypothalamus (VMH) are not well understood. There is evidence that VMH neurons play a relevant role in the modulation of unconditioned fear-related defensive behavioural reactions displayed by laboratory animals. OBJECTIVES: This study was designed to explore the specific pattern of distribution of the CB1 receptors in the VMH and to investigate the role played by this cannabinoid receptor in the effect of CBD on the control of defensive behaviours and unconditioned fear-induced antinociception. METHODS: A panic attack-like state was triggered in Wistar rats by intra-VMH microinjections of N-methyl-D-aspartate (NMDA). One of three different doses of CBD was microinjected into the VMH prior to local administration of NMDA. In addition, the most effective dose of CBD was used after pre-treatment with the CB1 receptor selective antagonist AM251, followed by NMDA microinjections in the VMH. RESULTS: The morphological procedures demonstrated distribution of labelled CB1 receptors on neuronal perikarya situated in dorsomedial, central and ventrolateral divisions of the VMH. The neuropharmacological approaches showed that both panic attack-like behaviours and unconditioned fear-induced antinociception decreased after intra-hypothalamic microinjections of CBD at the highest dose (100 nmol). These effects, however, were blocked by the administration of the CB1 receptor antagonist AM251 (100 pmol) in the VMH. CONCLUSION: These findings suggest that CBD causes panicolytic-like effects and reduces unconditioned fear-induced antinociception when administered in the VMH, and these effects are mediated by the CB1 receptor-endocannabinoid signalling mechanism in VMH.

Recent advances in LC-MS/MS methods to determine endocannabinoids in biological samples: Application in neurodegenerative diseases.

Endocannabinoids (ECs) are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors [cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2)]. Many ECs have been characterized; anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) are still considered the primary ECs signaling mediators. Dysregulation of ECs has been implicated in a wide range of pathologies, including neurodegenerative diseases. Understanding how ECs participate in neurological diseases is important to describe the pathology and to establish new treatments. Considering the physicochemical properties of ECs, liquid chromatography coupled to tandem mass spectrometry has become the reference method to determine these endogenous substances, in trace levels, in different biological samples. This review describes the recent advances in LC-MS/MS methods designed to determine ECs in complex biological matrixes. The advantages, limitations, selectivity, matrix effect, and sensitivity associated with each approach are emphasized. This article comprises three sections: (I) sample preparation techniques (conventional, microextraction, and online systems), (II) chromatographic methods (especially LC-MS/MS), and (III) relationship between ECs levels and neurodegenerative diseases.

Cavum septum pellucidum and adhesio interthalamica in schizophrenia: an MRI study.

Several studies have independently suggested that patients with schizophrenia are more likely to have an enlarged cavum septum pellucidum (CSP) and an absent adhesio interthalamica (AI), respectively. However, neither finding has been consistently replicated and it is unclear whether there is an association between these two midline brain abnormalities. Thus, we compared the prevalence of absent AI and the prevalence, size and volume of CSP in 38 patients with schizophrenia and 38 healthy controls using magnetic resonance imaging (MRI). There were no between group differences in the presence or volume of CSP; however, an enlarged CSP was commoner among patients than controls. There was also a positive correlation between CSP ratings and volumes. No differences in the presence or absence of the AI were found between patients and controls; however, an absent AI was commoner in male patients with schizophrenia than females. There was absolutely no overlap between the presence of a large CSP and an absence of AI. In conclusion, our findings are in line with several case series and other MRI investigations that have shown a higher incidence of putatively developmental brain abnormalities in patients with schizophrenia, particularly in males, and support the neurodevelopmental model of this disorder.

Dissociation between the panicolytic effect of cannabidiol microinjected into the substantia nigra, pars reticulata, and fear-induced antinociception elicited by bicuculline administration in deep layers of the superior colliculus: The role of CB1-cannabinoid receptor in the ventral mesencephalon.

Many studies suggest that the substantia nigra, pars reticulata (SNpr), a tegmental mesencephalic structure rich in γ-aminobutyric acid (GABA)- and cannabinoid receptor-containing neurons, is involved in the complex control of defensive responses through the neostriatum-nigral disinhibitory and nigro-tectal inhibitory GABAergic pathways during imminently dangerous situations. The aim of the present work was to investigate the role played by CB1-cannabinoid receptor of GABAergic pathways terminal boutons in the SNpr or of SNpr-endocannabinoid receptor-containing interneurons on the effect of intra-nigral microinjections of cannabidiol in the activity of nigro-tectal inhibitory pathways. GABAA receptor blockade in the deep layers of the superior colliculus (dlSC) elicited vigorous defensive behaviour. This explosive escape behaviour was followed by significant antinociception. Cannabidiol microinjection into the SNpr had a clear anti-aversive effect, decreasing the duration of defensive alertness, the frequency and duration of defensive immobility, and the frequency and duration of explosive escape behaviour, expressed by running and jumps, elicited by transitory GABAergic dysfunction in dlSC. However, the innate fear induced-antinociception was not significantly changed. The blockade of CB1 endocannabinoid receptor in the SNpr decreased the anti-aversive effect of canabidiol based on the frequency and duration of defensive immobility, the frequency of escape expressed by running, and both the frequency and duration of escape expressed by jumps. These findings suggest a CB1 mediated endocannabinoid signalling in cannabidiol modulation of panic-like defensive behaviour, but not of innate fear-induced antinociception evoked by GABAA receptor blockade with bicuculline microinjection into the superior colliculus, with a putative activity in nigro-collicular GABAergic pathways.

Performance anxiety in Brazilian musicians: prevalence and association with psychopathology indicators.

BACKGROUND: Musical performance anxiety (MPA) refers to persistent and distressing apprehension associated with performing to an audience. Our objective was to assess the presence of MPA and other psychopathologies in musicians and find correlations between socio-demographic and clinical variables. METHODS: We assessed 230 musicians using self-rated instruments whose results were statistically compared. The logistic regression was used to check for predictors of MPA. RESULTS: 24% of musicians had MPA indicators, 19% had indicators of social anxiety, and 20% of depression. These figures were even higher in the comparison between professional and amateur musicians, where the rates were doubled. In the logistic regression, gender and professional status did not predict MPA, but did predict social anxiety (OD=3.22; p=0.006) and depression (OD=3.87; p=0.003). CONCLUSIONS: We conclude that there is a high rate of psychiatric indicators among musicians, who have been dealing not only with difficulties inherent to their occupation, but also with under-recognized comorbidities with the potential to affect their personal and professional life in specific, poorly investigated ways. LIMITATIONS: It should be noted that our results must be interpreted with caution as we used screening and not diagnostic instruments, and because of the fact that our sample was restricted to the Brazilian context. Also, the role of temperamental features that could have a positive association with the condition of musician-and therefore minimize performance anxiety-could have been explored in order to provide a deeper understanding of the topic.

Olanzapine, weight change and metabolic effects: a naturalistic 12-month follow up.

OBJECTIVE: Olanzapine is an atypical antipsychotic drug used to treat schizophrenia. Some of the adverse effects related to its use are obesity, hyperlipidemia, type 2 diabetes and hypertension, which may result in development of metabolic syndrome. This study aimed to investigate a possible increase in some anthropometric and biochemical parameters, and the existence of any correlation between them in Brazilian patients with schizophrenia treated with olanzapine in the mid term. METHODS: Thirty subjects with schizophrenia were evaluated, 16 women and 14 men, aged between 18 and 47 years. All patients underwent blood collection and anthropometric measurements at four different times during 12 months of follow up; thus each patient was his or her own control. RESULTS: Evaluation of some anthropometric measurements showed significant differences when comparing the mean values obtained in each of the different data collection times (p < 0.05). However, the biochemical indicators of development of metabolic syndrome measured in our study did not show the same rate of increment, with only the total cholesterol and glucose levels presenting statistically significant changes (p < 0.05), but without the same magnitude of weight change. CONCLUSION: We conclude that medium-term treatment with olanzapine promoted a substantial weight gain and increased visceral fat, while the metabolic profile did not show the same magnitude of change, suggesting a dissociation between weight gain and blood parameters, despite the severe weight gain observed among subjects evaluated.

Cannabidiol and endogenous opioid peptide-mediated mechanisms modulate antinociception induced by transcutaneous electrostimulation of the peripheral nervous system.

Transcutaneous electrical nerve stimulation (TENS) is a non-pharmacological therapy for the treatment of pain. The present work investigated the effect of cannabidiol, naloxone and diazepam in combination with 10 Hz and 150 Hz TENS. Male Wistar rats were submitted to the tail-flick test (baseline), and each rodent received an acute administration (intraperitoneal) of naloxone (3.0mg/kg), diazepam (1.5mg/kg) or cannabidiol (0.75 mg/kg, 1.5mg/kg, 3.0mg/kg, 4.5mg/kg, 6.0mg/kg and 12.0mg/kg); 10 min after the acute administration, 10 Hz or 150 Hz TENS or a sham procedure was performed for 30 min. Subsequently, tail-flick measures were recorded over a 90-min period, at 5-min intervals. 10 Hz TENS increased the nociceptive threshold during the 90-min period. This antinociceptive effect was reversed by naloxone pre-treatment, was not altered by diazepam pre-treatment and was abolished by cannabidiol pre-treatment (1.5mg/kg). Moreover, 150 Hz TENS increased tail-flick latencies by 35 min post-treatment, which was partially inhibited by naloxone pre-treatment and totally inhibited by cannabidiol (1.5mg/kg). These data suggest the involvement of the endogenous opioid system and the cannabinoid-mediated neuromodulation of the antinociception induced by transcutaneous electrostimulation at 10 Hz and 150 Hz TENS.