The Endocannabinoid System as a Biomarker for Diagnostic and Therapeutic Applications in Depression and Anxiety.

BACKGROUND: Depression and anxiety belong to a family of mental disturbances that have increased significantly in recent years. The etiology of both disorders comprises multiple and complex factors, from genetic background to environmental influence. Since depression and anxiety present severe symptoms, they represent a greater clinical burden and greater therapeutic difficulty. Currently, standardized diagnostic procedures for depression and anxiety allow for the addition of further treatments, including psychotherapy and/or pharmacological intervention, with effective outcomes. However, further steps should be considered with regard to consideration of the endocannabinoid system's role in depression and anxiety. OBJECTIVE: This study aimed to review the evidence from animal research and clinical studies on the role of cannabinoid receptors, the major endocannabinoids -anandamide (AEA) and 2-arachidonoylglycerol (2-AG)- and the enzymes related to the synthesis and degradation of these chemicals as putative biomarkers for diagnostic and therapeutic elements of depression and anxiety. METHODS: This review included the online search, identification, and analysis of articles (basic and clinical trials) published in English in PubMed linked to the role of cannabinoid receptors, AEA, 2- AG, and the enzymes associated with the synthesis and degradation of these endocannabinoids in depression and anxiety. RESULTS: The neurobiological relevance of the endocannabinoid system offers genetic or pharmacological manipulation of this system as a potential strategy for the diagnostic and clinical management of mood disorders, including depression and anxiety. CONCLUSION: Although the described approach in this review is promising, no solid evidence is yet available, and along with additional experiments using animal models that mimic human depression and anxiety, clinical trials are needed to explore the role of the endocannabinoid system's elements as well as the anandamide membrane transporter, none of which have been adequately studied in depression and anxiety.

Clinical applications of exercise in Parkinson's disease: what we need to know?

INTRODUCTION: Exploring the potential of exercise in the rehabilitation process of patients with Parkinson's (PD) may be an interesting treatment perspective. Exercise-induced responses derived from neurotrophic elements appear to ameliorate the decline in neurodegeneration. Despite this understanding, the literature needs to be updated. AREAS COVERED: Our review focuses on: a) the key mechanisms of exercise on PD, highlighting mainly the responses related to neuroplasticity; b) the effects induced by different traditional types of exercise, also highlighting the effects of complementary therapies related to movement; c) the volume of exercise required to support efficient results are explored in the context of PD. Additionally, the proposition of new clinical application strategies in the context of PD will also be determined. EXPERT OPINION: It is suggested that different intensities of aerobic exercise be explored for the treatment of PD. The results associated with high intensity seem promising for performance, physiological and clinical parameters, such as BDNF production and cognition. On the other hand, the diversification of tasks and repetition of motor gestures appear as consistent arguments to exercise prescription. Finally, for future investigations, the neuromodulation strategy in association with aerobic exercise appears as a potential inducer of benefits on gait and cognitive function.

Neurobiology of Dream Activity and Effects of Stimulants on Dream.

The sleep-wake cycle is the result of the activity of multiple neurobiological network interactions. The dreaming feature is one interesting sleep on that represents sensorial components, mostly visual perceptions, accompaniedby intense emotions. Further complexity has been added to the topic of the neurobiological mechanism of dream generation by the current data suggesting drugs' influence on dream generation. Here, we discuss the review of some of the neurobiological mechanisms of the regulation of dream activity, with special emphasis on the effects of stimulants on dreaming.

Mental health and social isolation under repeated mild lockdowns in Japan.

The influence of repeated lockdowns on mental health and social isolation is unknown. We conducted a longitudinal study of the influence of repeated mild lockdowns during two emergency declarations in Japan, in May 2020 and February 2021. The analyses included 7893 people who participated in all online surveys. During repeated mild lockdowns, mental and physical symptoms decreased overall, while loneliness increased and social networks decreased. Subgroup analyses revealed that depression and suicidal ideation did not decrease only in the younger age group (aged 18-29 years) and that younger and middle-aged people (aged 18-49 years), women, people with a history of treatment for mental illness, and people who were socially disadvantaged in terms of income had higher levels of mental and physical symptoms at all survey times. Additionally, comprehensive extraction of the interaction structure between depression, demographic attributes, and psychosocial variables indicated that loneliness and social networks were most closely associated with depression. These results indicate that repeated lockdowns have cumulative negative effects on social isolation and loneliness and that susceptible populations, such as young people and those with high levels of loneliness, require special consideration during repeated lockdown situations.

Personalization of Pharmacological Treatments for ADHD: Why it is Advisable and Possible Options to Achieve it.

Attention-deficit hyperactivity disorder is a neurodevelopmental disorder diagnosed primarily in children, although it is also present in adults. Patients present inattention, impulsivity, and hyperactivity symptoms that create difficulties in their daily lives. Pharmacological treatment with stimulants or non-stimulants is used most commonly to reduce ADHD symptoms. Although generally effective and safe, pharmacological treatments have different effects among patients, including lack of response and adverse reactions. The reasons for these differences are not fully understood, but they may derive from the highly diverse etiology of ADHD. Strategies to guide optimal pharmacological treatment selection based on individual patients' physiological markers are being developed. In this review, we describe the main pharmacological ADHD treatments used and their main drawbacks. We present alternatives under study that would allow the customization of pharmacological treatments to overcome these drawbacks and achieve more reliable improvement of ADHD symptoms.

Decreased Resting State Inter- and Intra-Network Functional Connectivity Is Associated with Perceived Stress in a Sample of University Students: An eLORETA Study.

INTRODUCTION: Although the study of the Triple Network (TN) model has gained attention in the exploration of stress-related processes, the neurophysiological mechanisms of TN in relation to perceived stress have been relatively understudied in nonclinical samples so far. The main objective of the present study was to investigate, in a sample of university students, the association of perceived stress with resting state electroencephalography (EEG) functional connectivity in the TN. METHODS: Ninety university students (40 males and 50 females; mean age 22.30 ± 2.43 years; mean educational level 16.60 ± 1.62 years) were enrolled. EEG data were analyzed through the exact low-resolution electromagnetic tomography (eLORETA). RESULTS: Higher levels of perceived stress were associated with decreased delta EEG connectivity within the central executive network (CEN) and between the CEN and the salience network (SN). Higher levels of perceived stress were also associated with decreased theta EEG connectivity between the CEN and the SN. The associations between perceived stress and EEG connectivity data were significant even when relevant confounding factors (i.e., sex, age, educational level, and psychopathological symptoms) were controlled for. DISCUSSION: Taken together, our results suggest that higher levels of perceived stress are associated with a dysfunctional synchronization within the CEN and between the SN and the CEN. This functional pattern might in part reflect the negative impact of high levels of perceived stress on cognitive functioning.

Stimulants and Depressor Drugs in the Sleep-wake Cycle Modulation: The Case of Alcohol and Cannabinoids.

A complex neurobiological network drives the sleep-wake cycle. In addition, external stimuli, including stimulants or depressor drugs, also influence the control of sleep. Here we review the recent advances that contribute to the comprehensive understanding of the actions of stimulants and depressor compounds, such as alcohol and cannabis, in sleep regulation. The objective of this review is to highlight the neurobiological mechanism engaged by alcohol and cannabis in sleep control.

Can regular physical exercise be a treatment for panic disorder? A systematic review.

INTRODUCTION: In the last few decades, exercise has been explored as a potential tool to reduce symptoms experienced by patients with panic disorder (PD). This systematic review aims to assess the effects of regular exercise interventions on panic severity, global anxiety, and depression symptoms of these patients. AREAS COVERED: A search was conducted on PubMed, ISI Web of Science, and Cochrane Central Register of Controlled Trials using search terms related to PD and exercise. Eight trials were included, Furthermore, regular exercise programs presented different methodological characteristics. There is o clear evidence indicating that regular exercise programs (at least two 20-minute sessions per week for at least 6 weeks) reduce panic-related symptoms. Regular exercise is effective in improving global anxiety measures and depression. EXPERT OPINION: Continuous aerobic exercise is the main type of intervention in the literature, generally providing a limited prescription. Currently, it is recommended the interval training, with intense and shorter stimuli, and long-term duration trials. However, despite the use of self-selected intensities and control based on the internal load be interesting as recommendation to increase adherence, careful is needed regarding training prescription due to scarce evidence.

Health-Related Fitness as a Predictor of Anxiety Levels Among School Adolescents: An observational cross-sectional study.

Background: There is an inverse association between cardiorespiratory fitness and general anxiety levels in adolescents. Obesity also is associated with a higher risk of anxiety in this population. However, little is known about the association between other health-related fitness elements with anxiety symptoms in this population. The authors explored the relationship between health-related fitness and anxiety symptoms in a large sample of Brazilian youth. Methods: This was an observational cross-sectional study with a sample comprised of 257 school adolescents, who were 136 girls (52.9%) and 121 boys (47.1%). The health-related fitness elements were evaluated by FitnessGram® test and anxiety levels by Multidimensional Anxiety Scale for Children - 39. Hierarchical regression analyses were used to determine the association between health-related fitness elements and anxiety symptoms in both sexes. Results: In male adolescents, only the cardiorespiratory fitness was significantly associated with anxiety symptoms (F(1, 119) = 6.472; P = 0.012; R2 = 0.052; adjusted R2 = 0.044). In turn, the anxiety symptoms showed an inverse small relationship with cardiorespiratory fitness (r = - 0.227; P < 0.01). However, in female adolescents, no association was found between health-related fitness elements and anxiety symptoms. Conclusion: The level of cardiorespiratory fitness may represent a marker of anxiety in male adolescents.

The Endocannabinoid System as Prognostic Biomarker of the Obstructive Sleep Apnea Morbidity in COVID-19-Recovered Individuals.

The endocannabinoid system is a neurobiological signaling network that is present in the human biological systems, including the brain. This neurobiological system comprises cannabinoid receptors, endogenous ligands, as well as enzymatic synthesis, degradation and transport of endocannabinoids and has been suggested as a modulator of multiple physiological processes, including the sleep-wake cycle. On the other hand, the COVID-19 pandemic, originated by the novel coronavirus SARS-CoV-2, has caused global catastrophes in economic, social, and health spheres. COVID-19 is a multi-organ disease with a broad spectrum of health complications, such as respiratory infections leading to respiratory-related symptoms and disorders. The development, approval, and application of vaccines against SARS-CoV-2 is ongoing; however, there are increasing reports of prolonged effects after COVID-19 infection, including respiratory and neurological sequelae. Here, I provide a comprehensive review of the current literature on the endocannabinoid system and their role in sleep modulation. Whilst I discuss relevant considerations for the high risk for developing sleep disorders related to respiratory failures, such as obstructive sleep apnea (OSA) in recovered COVID-19-infected subjects. Finally, I propose a framework that integrates the analysis of the components of the endocannabinoid system as prognostic biomarkers of the likely OSA after COVID-19 infection.

Juvenile cannabidiol chronic treatments produce robust changes in metabolic markers in adult male Wistar rats.

The use of cannabidiol (CBD), the non-psychotropic compound derived from Cannabis sativa, for therapeutic purposes is growing exponentially by targeting the management of multiple medical disorders, including metabolic-related diseases. Nevertheless, substantial questions have emerged in concerning the potential metabolic disturbances in adulthood as consequence of the long-term uses of CBD during early years of life. Therefore, we studied whether chronic CBD injections (5, 10 or 30 mg/kg; i.p.) given to juvenile rats (from post-natal day [PND] 30) for 14 days might influence in adulthood the activity of metabolic markers, such as glucose, total cholesterol, triglycerides as well as activity of antioxidants (DPPH) from plasma, white adipose tissue (WAT), brown adipose tissue (BAT), liver, and hypothalamus. Our results showed that adult rats treated during juvenile ages with CBD (5, 10 or 30 mg/kg) for two weeks increased the contents of glucose whereas with no changes on total cholesterol in adulthood were observed. Additionally, a significant decrease in the levels of triglycerides were found in plasma, WAT, BAT, and liver in adult rats treated with chronic injections of CBD during the adolescence. However, unexpectedly, the contents of triglycerides in hypothalamus were found enhanced. Finally, the DPPH assay showed a significant enhancement in triglycerides analyzed from WAT and liver whereas opposite findings were observed in BAT and no significant changes were found in hypothalamus in adult rats that received during the adolescence chronic injections of CBD. In conclusion, repeated CBD administration to juvenile rats induced significant alterations in multiple metabolic markers analyzed in the adulthood. Our findings highlight the relevance of chronic CBD treatment in disturbed metabolic activity and remark the need for studying the underlying mechanisms involved.

In vivo brain levels of acetylcholine and 5-hydroxytryptamine after oleoylethanolamide or palmitoylethanolamide administrations are mediated by PPARα engagement.

The peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor that has been linked to the modulation of several physiological functions, including the sleep-wake cycle. The PPARα recognizes as endogenous ligands the lipids oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), which in turn, if systemically injected, they exert wake-promoting effects. Moreover, the activation of PPARα by the administration of OEA or PEA increases the extracellular contents of neurotransmitters linked to the control of wakefulness; however, the role of PPARα activated by OEA or PEA on additional biochemicals related to waking regulation, such as acetylcholine (ACh) and 5-hydroxytryptamine (5-HT), has not been fully studied. Here, we have investigated the effects of treatments of OEA or PEA on the contents of ACh and 5-HT by using in vivo microdialysis techniques coupled to HPLC means. For this purpose, OEA or PEA were systemically injected (5, 10 or 30 mg/kg; i.p.), and the levels of ACh and 5-HT were collected from the basal forebrain, a wake-related brain area. These pharmacological treatments significantly increased the contents of ACh and 5-HT as determined by HPLC procedures. Interestingly, PPARα antagonist MK-886 (30 mg/kg; i.p.) injected before the treatments of OEA or PEA blocked these outcomes. Our data suggest that the activation of PPARα by OEA or PEA produces significant changes on ACh and 5-HT levels measured from the basal forebrain and support the conclusion that PPARα is a suitable molecular element involved in the regulation of wake-related neurotransmitters.

Assessing the treatment of cannabidiolic acid methyl ester: a stable synthetic analogue of cannabidiolic acid on c-Fos and NeuN expression in the hypothalamus of rats.

BACKGROUND: Cannabidiol (CBD), the non-psychotropic compound from Cannabis sativa, shows positive results on controlling several health disturbances; however, comparable data regarding additional chemical from C. sativa, such as cannabidiolic acid (CBDA), is scarce due to its instability. To address this limitation, a stable CBDA analogue, CBDA methyl ester (HU-580), was synthetized and showed CBDA-like effects. Recently, we described that HU-580 increased wakefulness and wake-related neurochemicals. OBJECTIVE: To extend the comprehension of HU-580´s properties on waking, the c-Fos and NeuN expression in a wake-linked brain area, the hypothalamus was evaluated. METHODS: c-Fos and NeuN expression in hypothalamic sections were analyzed after the injections of HU-580 (0.1 or 100 µg/kg, i.p.). RESULTS: Systemic administrations of HU-580 increased c-Fos and neuronal nuclei (NeuN) expression in hypothalamic nuclei, including the dorsomedial hypothalamic nucleus dorsal part, dorsomedial hypothalamic nucleus compact part, and dorsomedial hypothalamic nucleus ventral part. CONCLUSION: HU-580 increased c-Fos and NeuN immunoreactivity in hypothalamus nuclei suggesting that this drug might modulate the sleep-wake cycle by engaging the hypothalamus.

Does Dysbiosis Increase the Risk of Developing Schizophrenia? - A Comprehensive Narrative Review.

BACKGROUND: There is increasing evidence regarding the influence of the intestinal microbiota on the disease processes of various organs and systems. Dysbiosis, that is, alteration of the composition and function of the microbiota may constitute an important risk factor for the development of mental disorders, namely, schizophrenia. OBJECTIVE: This works aims to review current evidence regarding the pathological mechanisms leading from dysbiosis to schizophrenia and in particular the deficit syndrome in schizophrenia. METHODS: Scientific articles from PubMed, SCOPUS, EMBASE, and Web of Science Core Collection published between September 2017 and December 2020 were included in this review. RESULTS: The commensal intestinal flora plays an important role in neurodevelopment. In the presence of dysbiosis, this maturation gets disturbed, resulting in the modification of brain structures and inflammatory responses at the intestinal, systemic, and Central Nervous System (CNS) levels. These disturbances may be linked to the development of symptoms of the disease. The microbiota exerts its influence on the CNS through several pathways, however, in this paper we focused on the membrane hypothesis and the inflammatory hypothesis. We explored the evidence concerning the use of probiotics, prebiotics, and fecal transplants. CONCLUSION: Although there is no consensus regarding the alterations that could constitute a risk factor for schizophrenia, some of the species appear to be more frequently altered, and their relationship with the host is dysregulated in patients at risk and with established schizophrenia, particularly in deficit schizophrenia.

The Role of Peroxisome Proliferator-Activated Receptor in Addiction: A Novel Drug Target.

The peroxisome proliferator activated receptors (PPARs) are a superfamily of well-recognized ligand-binding nuclear receptors comprising three isoforms: PPARα, PPARγ, and PPARß/δ. In response to endogenous lipid messengers, PPARs trigger the transcription of genes related to a wider spectrum of physiological phenomena, including fatty acid oxidation, inflammation, adipogenesis, among many others. Thus, the importance of PPARs as putative protective therapy in health issues has increased the interest of studying these nuclear receptors, including the management of neurodegenerative disorders, multiple sclerosis, and likely addiction. In recent years, several pieces of evidence from animal models have demonstrated the promising role of PPARs as a critical element for interventions in addictive behaviors by reducing the reinforcing properties of addictive substances such as alcohol. However, there is a lack of data in the scope and has so far been unexplored the function of PPARs in additional drugs such as cannabis, opioids, methamphetamine, or cocaine. A similar scenario has been found for the management of binge-type eating disorders. Thus, here we review recent advances in understanding the relevance of the PPAR controlling addiction.

Physical Activity, Boredom and Fear of COVID-19 Among Adolescents in Germany.

BACKGROUND: The effectiveness of physical activity (PA) as an intervention against anxiety disorders and depression is undeniable in clinical psychology. Therefore, the question arose whether these effects also occur when a fear stimulus, like the COVID-19 pandemic, affects otherwise healthy adolescents. Boredom is closely linked to symptoms of fear and anxiety, but the connection between PA, boredom and fear is partly unclear. METHODS: A cross-sectional online study was conducted that involved 122 students. Participants were 13-19 years old (M age = 15.83, SD = 1.73). The survey was available online from April 27th to May 3rd, 2020. At this time, schools in Germany had already been closed for 6 weeks. A self-report questionnaire was used to measure physical activity, boredom, and fear of COVID-19. A multiple linear regression model was conducted. RESULTS: The reported fear of COVID-19 significantly correlates with total PA, quantity of strenuous PA, and boredom. Furthermore, a significant regression equation was found. The variables boredom, PA, and age contribute significantly to predicting the fear of COVID-19 [R 2 = 0.127, F(3,118) = 6.876, p < 0.000], among adolescents. CONCLUSION: Our results indicate that there is an association between PA, boredom and the quarantine experience of adolescents. Students who were physically more active, especially with strenuous intensity, did not feel bored and showed less fear of COVID-19.

The synthetic CB1 cannabinoid receptor selective agonists: Putative medical uses and their legalization.

More than 500 molecules have been identified as components of Cannabis sativa (C. sativa), of which the most studied is Δ9-tetrahydrocannabinol (Δ9-THC). Several studies have suggested that Δ9-THC exerts diverse biological effects, ranging from fragmentation of DNA to behavioral disruptions. Currently, it is accepted that most of the pharmacological properties of Δ9-THC engage the activation of the cannabinoid receptors, named CB1 and CB2. Interestingly, multiple pieces of evidence have suggested that the cannabinoid receptors play an active role in the modulation of several diseases leading to the design of synthetic cannabinoid-like compounds. Advances in the development of synthetic CB1 cannabinoid receptor selective agonists as therapeutical approaches are, however, limited. This review focuses on available evidence searched in PubMed regarding the synthetic CB1 cannabinoid receptor selective agonists such as AM-1235, arachidonyl-2' chloroethylamide (ACEA), CP 50,556-1 (Levonantradol), CP-55,940, HU-210, JWH-007, JWH-018, JWH-200 (WIN 55,225), methanandamide, nabilone, O-1812, UR-144, WIN 55,212-2, nabiximols, and dronabinol. Indeed, it would be ambitious to describe all available evidence related to the synthetic CB1 cannabinoid receptor selective agonists. However, and despite the positive evidence on the positive results of using these compounds in experimental models of health disturbances and preclinical trials, we discuss evidence in regards some concerns due to side effects.

Sleep-wake cycle disturbances and NeuN-altered expression in adult rats after cannabidiol treatments during adolescence.

RATIONALE: The medical uses of cannabidiol (CBD), a constituent of the Cannabis sativa, have accelerated the legal and social acceptance for CBD-based medications but has also given the momentum for questioning whether the long-term use of CBD during the early years of life may induce adverse neurobiological effects in adulthood, including sleep disturbances. Given the critical window for neuroplasticity and neuro-functional changes that occur during stages of adolescence, we hypothesized that CBD might influence the sleep-wake cycle in adult rats after their exposure to CBD during the adolescence. OBJECTIVES: Here, we investigated the effects upon behavior and neural activity in adulthood after long-term administrations of CBD in juvenile rats. METHODS: We pre-treated juvenile rats with CBD (5 or 30 mg/Kg, daily) from post-natal day (PND) 30 and during 2 weeks. Following the treatments, the sleep-wake cycle and NeuN expression was analyzed at PND 80. RESULTS: We found that systemic injections of CBD (5 or 30 mg/Kg, i.p.) given to adolescent rats (post-natal day 30) for 14 days increased in adulthood the wakefulness and decreased rapid eye movement sleep during the lights-on period whereas across the lights-off period, wakefulness was diminished and slow wave sleep was enhanced. In addition, we found that adult animals that received CBD during the adolescence displayed disruptions in sleep rebound period after total sleep deprivation. Finally, we determined how the chronic administrations of CBD during the adolescence affected in the adulthood the NeuN expression in the suprachiasmatic nucleus, a sleep-related brain region. CONCLUSIONS: Our findings are relevant for interpreting results of adult rats that were chronically exposed to CBD during the adolescence and provide new insights into how CBD may impact the sleep-wake cycle and neuronal activity during developmental stages.