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.

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.

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.

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.

Effects on the Post-translational Modification of H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 Levels in Cerebral Cortex, Hypothalamus and Pons of Rats after a Systemic Administration of Cannabidiol: A Preliminary Study.

BACKGROUND: Cannabidiol (CBD), a non-psychotropic constituent of Cannabis sativa, has shown therapeutic promises by modulating several pathological conditions, including pain, epilepsy autism, among others. However, the molecular mechanism of action of CBD remains unknown and recent data suggest the engagement on CBD´s effects of nuclear elements, such as histone activity. AIM: This study assessed the changes in the post-translational modification (PTM) on the histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 in several brain regions of rats after the administration of CBD (20 mg/Kg/i.p.). OBJECTIVE: To evaluate the effects on the PTM of histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 levels in the cerebral cortex, hypothalamus and pons of CBD-treated rats. METHODS: Ten adult rats were randomly assigned into 2 groups: Control or CBD (20 mg/Kg/i.p). Animals were sacrificed after treatments and brains were collected for dissections of the cerebral cortex, hypothalamus and pons. Samples were analyzed for PTM on the histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 levels by Western blot procedure. RESULTS: CBD increased the PTM levels on the histones H3K4Me3, H3K9ac, and H3K27Me3 in the cerebral cortex whereas no significant differences were found in H3K9Me2 and H3K36Me2. In addition, in the hypothalamus, CBD decreased the contents of H3K9ac while no significant effects were observed in H3K4Me3, H3K9Me2, H3K27Me3, and H3K36Me2. Lastly, in the pons, CBD- treated rats showed a significant decline on the PTM levels of H3K4Me3 whereas no statistical differences were found in H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2. CONCLUSION: The study showed that CBD induced differential effects in levels of PTM on the histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 in several brain regions.

Physical exercise and geriatric depression: an opinion / Atividade física e depressão geriátrica: uma opinião / Actividad física y depresión geriátrica: una opinión

Depression represents a common public health problem in the world. Depression in the elderly appears to follow a vulnerability-stress model, with an interaction between individual vulnerabilities, including genetic factors, age-related cognitive and neurobiological changes, and a variety of stressful events that occur more frequently in advanced ages, such as grief, financial problems, and reduction in autonomy/functionality. In the last decades, several studies have indicated that exercise can be effective in preventing or reducing depressive symptoms, both in healthy and psychiatric populations. Due to the scientific community's interest in the efficacy and safety of physical exercise as complementary therapy for depressed elderly patients, we conduct an opinion study on the subject. Despite the researchers' efforts, in the last decades little progress has been made in verifying the efficacy of exercise in geriatric depression.

A depressão representa um problema comum de saúde pública no mundo. A depressão em idosos parece seguir um modelo de vulnerabilidade-estresse, com uma interação entre vulnerabilidades individuais, incluindo fatores genéticos, mudanças cognitivas e neurobiológicas relacionadas à idade, e uma variedade de eventos estressantes que ocorrem mais frequentemente em idades avançadas, como luto, problemas financeiros e redução da autonomia/funcionalidade. Nas últimas décadas, vários estudos indicaram que o exercício pode ser eficaz na prevenção ou redução dos sintomas depressivos, tanto em populações saudáveis como psiquiátricas. Devido ao interesse da comunidade científica na eficácia e segurança do exercício físico como terapia complementar para idosos deprimidos; realizamos um estudo de opinião sobre o assunto. Apesar dos esforços dos pesquisadores, nas últimas décadas pouco progresso foi feito na verificação da eficácia do exercício na depressão geriátrica.

La depresión representa un problema común de salud pública en el mundo. La depresión en los ancianos parece seguir un modelo de vulnerabilidad-estrés, con una interacción entre las vulnerabilidades individuales, incluidos factores genéticos, cambios cognitivos y neurobiológicos relacionados con la edad, y una variedad de eventos estresantes que ocurren con mayor frecuencia en edades avanzadas, como el duelo, problemas financieros y reducción de la autonomía/funcionalidad. En las últimas décadas, varios estudios han indicado que el ejercicio puede ser eficaz para prevenir o reducir los síntomas depresivos, tanto en poblaciones sanas como psiquiátricas. Debido al interés de la comunidad científica en la eficacia y seguridad del ejercicio físico como terapia complementaria para pacientes ancianos deprimidos, realizamos un estudio de opinión sobre el tema. A pesar de los esfuerzos de los investigadores, en las últimas décadas se ha avanzado poco en la verificación de la eficacia del ejercicio en la depresión geriátrica.

Cannabidiol Partially Blocks the Excessive Sleepiness in Hypocretindeficient Rats: Preliminary Data.

BACKGROUND: Excessive daytime sleepiness and cataplexy are among the symptoms of narcolepsy, a sleep disorder caused by the loss of hypocretin/orexin (HCRT/OX) neurons placed into the Hypothalamus (LH). Several treatments for managing narcolepsy include diverse drugs to induce alertness, such as antidepressants, amphetamine, or modafinil, etc. Recent evidence has shown that cannabidiol (CBD), a non-psychotropic derived from Cannabis sativa, shows positive therapeutic effects in neurodegenerative disorders, including Parkinson´s disease. Furthermore, CBD provokes alertness and enhances wake-related neurochemicals in laboratory animals. Thus, it is plausible to hypothesize that excessive somnolence observed in narcolepsy might be blocked by CBD. OBJECTIVE: Here, we determined whether the systemic injection of CBD (5mg/kg, i.p.) would block the excessive sleepiness in a narcoleptic model. METHODS: To test this idea, the neurotoxin hypocretin-2-saporin (HCRT2/SAP) was bilaterally injected into the LH of rats to eliminate HCRT leading to the establishment of narcoleptic-like behavior. Since excessive somnolence in HCRT2/SAP lesioned rats has been observed during the lights-off period, CBD was administered at the beginning of the dark phase. RESULTS: Hourly analysis of sleep data showed that CBD blocked the sleepiness during the lights-off period across 7h post-injection in lesioned rats. CONCLUSION: Taking together, these preliminary findings suggest that CBD might prevent sleepiness in narcolepsy.

The artificial sweetener Splenda intake promotes changes in expression of c-Fos and NeuN in hypothalamus and hippocampus of rats.

BACKGROUND: Obesity is the result of the interaction of multiple variables, including the excessive increase of sugar-sweetened beverages consumption. Diets aimed to treat obesity have suggested the use of artificial sweeteners. However, recent evidence has shown several health deficits after intake of artificial sweeteners, including effects in neuronal activity. Therefore, the influence of artificial sweeteners consumption such as Splenda, on the expression of c-Fos and neuronal nuclear protein (NeuN) in hypothalamus and hippocampus remains to be determined. OBJECTIVES: We investigated the effects on c-Fos or NeuN expression in hypothalamus and hippocampus of Splenda-treated rats. METHODS: Splenda was diluted in water (25, 75 or 250 mg/100 mL) and orally given to rats during 2 weeks ad libitum. Next, animals were sacrificed by decapitation and brains were collected for analysis of c-Fos or NeuN immunoreactivity. RESULTS: Consumption of Splenda provoked an inverted U-shaped dose-effect in c-Fos expression in ventromedial hypothalamic nucleus while similar findings were observed in dentate gyrus of hippocampus. In addition, NeuN immunoreactivity was enhanced in ventromedial hypothalamic nucleus at 25 or 75 mg/100 mL of Splenda intake whereas an opposite effect was observed at 250 mg/100 mL of artificial sweetener consumption. Lastly, NeuN positive neurons were increased in CA2/CA3 fields of hippocampus from Splenda-treated rats (25, 75 or 250 mg/100 mL). CONCLUSION: Consuming Splenda induced effects in neuronal biomarkers expression. To our knowledge, this study is the first description of the impact of intake Splenda on c-Fos and NeuN immunoreactivity in hypothalamus and hippocampus in rats.

The impact of an exercise training intervention on cortisol levels and post-traumatic stress disorder in juveniles from an Ugandan refugee settlement: study protocol for a randomized control trial.

BACKGROUND: Latest research demonstrates a significant improvement in stress-related symptoms in psychological disorders as a result of exercise training (ET). Controlled clinical trials further validate the significance of ET by demonstrating lower salivary cortisol levels in patients with post-traumatic stress disorder (PTSD) after intervention. A significant change in cortisol and dehydroepiandrosterone (DHEA) levels can already be found after an 8-12-week ET program. The proposed study aims to investigate the impact of an 8-week ET on PTSD symptoms and changes in cortisol levels in a juvenile refugee sample from the Democratic Republic of the Congo (DRC) at an Ugandan refugee settlement. It is the first to implement an ET intervention in a resource-poor, post-conflict setting. METHODS/DESIGN: In a randomized controlled trial, 198 adolescent participants aged 13-16 years from the DRC who, suffer from PTSD, will be investigated. The participants are based at the Nakivale refugee settlement, an official refugee camp in Uganda, Africa, which is among the largest in the world. The participants will be randomized into an Exercise Training (ET) group with a maximum heart rate (HRmax) of > 60%, an Alternative Intervention (AI) group with low-level exercises, and a Waiting-list Control (WC) group. After the 8-week interventional phase, changes in cortisol awakening response (CAR) and DHEA in the ET group that correspond to an improvement in PTSD symptoms are expected that remain at follow-up after 3 months. DISCUSSION: To date, there is no controlled and reliable longitudinal study examining the effects of an ET program on symptom severity in individuals with PTSD that can be explained with a harmonization of cortisol secretion. The presented study design introduces an intervention that can be implemented with little expenditure. It aims to provide a promising low-threshold and cost-effective treatment approach for the application in resource-poor settings. TRIAL REGISTRATION: German Trials Register, ID: DRKS00014280 . Registered prospectively on 15 March 2018.

Effect of Heteropterys aphrodisiaca on Anxiety and Male Exposure of Female Mice with Advanced Age.

BACKGROUND: Effect of Heteropterys aphrodisiaca (dog-node) on anxiety and function of adult female wistar mice. The project is an experiment with the use of H. aphrodisiac root extract, in order to observe the frequency of sexual exposure of females exposed to the extract, quantify the effect of the extract on the concentration of total testosterone and observe the anxiety levels of the animals exposed. Results will be measured with the laboratory testosterone test and LCE and CA tests. METHODS: In preparation of the extract, the root was oven dried at 40°C and diluted in alcohol extract (100g of root for 1 liter of alcohol) and lyophilized. 40 adult female mice were enrolled, separated in control group (placebo) and treatment group (50 mg/kg/day) for 15, 30, 45 and 60 days. At each period, hormonal testosterone and anxiety levels by the Elevated-Cross Labyrinth (ECL) tests and Open Camp (CA) were measured in 10 animals that were later euthanized (SBNeC). RESULTS: The results showed an improvement in the decrease of anxiety, as shown in the variables of number of open arm entries, time on the same side of the field, less avoidance and leakage. However, it appears that the time of exposure to the extract does not result in increased benefit, with possible decline of effect after 45 days of use. CONCLUSION: With this performed experiment with the "no-de-cachorro" extract, it was possible to understand a little more how this root can act in relation to anxiety, as predicted by the pharmacology that validates the animal models; anxiolytic components decrease anxiety-related behaviors, as shown in the variables of entry numbers in the open arm, time on the same side of the field, less avoidance and escape. However, it seems that the time of exposure to the extract does not modify the performance in the tests, observing until an apparent exhaustion of the anxiolytic action, which evidences the need for more specific studies on the possible effects of the extract.

Intrahypothalamic Administration of Modafinil Increases Expression of MAP-Kinase in Hypothalamus and Pons in Rats.

Modafinil (MOD) it has to be considered as a wake-inducing drug to treat sleep disorders such as excessive sleepiness in narcolepsy, shift-work disorder, and obstructive/sleep apnea syndrome. Current evidence suggests that MOD induces waking involving the dopamine D1 receptor. However, little is known regarding the molecular elements linked in the wake-promoting actions of MOD. Since the D1 receptor activates the mitogen-activated protein kinase (MAP-K) cascade, it raises the interesting possibility that effects of MOD would depend upon the activation of MAP-K. Here we tested the expression of MAP-K in hypothalamus as well as pons after the microinjection of MOD (10 or 20 µg/1 µL) in rats into anterior hypothalamus, a wake-inducing brain area. Intrahypothalamic injections of MOD promoted MAP-K phosphorylation in hypothalamus and pons. Taken together, these results suggest that the wake-inducing compound MOD promotes the MAP-K phosphorylation.

Intrahypothalamic injection of cannabidiol increases the extracellular levels of adenosine in nucleus accumbens in rats.

Cannabidiol (CBD) is a constituent of Cannabis sativa that promotes wakefulness as well as enhances endogenous levels of wake-related neurotransmitters, including dopamine. However, at this date, the effects of CBD on the sleep-inducing molecules, such as adenosine (AD), are unknown. Here, we report that intrahypothalamic injection of CBD (10µg/1µL) increases the extracellular levels of AD collected from nucleus accumbens. Furthermore, the pharmacodynamic of this drug shows that effects on the contents of AD last 2h post-injection. These preliminary findings suggest that CBD promotes the endogenous accumulation of AD.

Effects of hypocretin/orexin cell transplantation on narcoleptic-like sleep behavior in rats.

The sleep disorder narcolepsy is now considered a neurodegenerative disease because there is a massive loss of neurons containing the neuropeptide hypocretin/orexin (HCRT). In consequence, narcoleptic patients have very low cerebrospinal fluid (CSF) levels of HCRT. Studies in animal models of narcolepsy have shown the neurophysiological role of the HCRT system in the development of this disease. For example, the injection of the neurotoxin named hypocretin-2-saporin (HCRT2/SAP) into the lateral hypothalamus (LH) destroys the HCRT neurons, therefore diminishes the contents of HCRT in the CSF and induces narcoleptic-like behavior in rats. Transplants of various cell types have been used to induce recovery in a variety of neurodegenerative animal models. In models such as Parkinson's disease, cell survival has been shown to be small but satisfactory. Similarly, cell transplantation could be employed to implant grafts of HCRT cells into the LH or even other brain regions to treat narcolepsy. Here, we report for the first time that transplantation of HCRT neurons into the LH of HCRT2/SAP-lesioned rats diminishes narcoleptic-like sleep behavior. Therefore, cell transplantation may provide an effective method to treat narcolepsy.

Co-enzyme Q10 to treat neurological disorders: basic mechanisms, clinical outcomes, and future research direction.

Coenzyme Q10 (CoQ10) is critical for the cell power supply in mitochondria. CoQ10 shuttles electrons from complexes I and II to complex III, and can be anti-oxdiative. Neurons require high energy for synaptic transmission and therefore the mitochondria dysfunction often leads to severe neuronal degeneration, as observed in many neurological disorders. CoQ10 supplementation has been widely used to treat aging, stroke, neuromuscular diseases, Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, autosomal recessive cerebellar ataxias, Huntington's disease and amyotrophic lateral sclerosis. Here we discuss a large number of preclinical and clinical trials for CoQ10 to elucidate the mechanisms underlying CoQ10 therapy. The rational applications as a therapeutic agent in neurological disorders are discussed.

Brain molecules and appetite: the case of oleoylethanolamide.

The neurobiological mechanisms of feeding involve the activity of several brain areas as well as the engagement of endogenous compounds such as ghrelin, melanin-concentrating hormone, orexin, neuropeptide Y, leptin, vasoactive intestinal peptide, cholecystokinin, among others. Furthermore, the family of food-intake modulators has been enlarged due to the inclusion of lipids such as N-arachidonoylethanolamide (anandamide), as well as oleoylethanolamide (OEA). In this regard, the food-intake suppressing properties of OEA have been described since pharmacological administration of this compound induces anorexia. It has been suggested that satiety induced by OEA may be through the activation of peroxisome proliferator-activated receptor-α (PPAR-α), a ligand-activated transcription factor that modulates several pathways of lipid metabolism. The mechanism of action of OEA remains unknown, it has been suggested that the ingestion of dietary fat stimulates epithelial cells of the small intestine and promotes the synthesis and release of OEA. Upon its release, this lipid acts within the gut engaging sensory fibers of the vagus nerve to diminish food-intake. Here, recent advances in our understanding of the neurobiological role of OEA in modulation of feeding will be reviewed. Also, we highlight the emerging molecular mechanism of anorexia induced by OEA.

Administration of URB597, oleoylethanolamide or palmitoylethanolamide increases waking and dopamine in rats.

BACKGROUND: Oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) are amides of fatty acids and ethanolamine named N-acylethanolamines or acylethanolamides. The hydrolysis of OEA and PEA is catalyzed by the fatty acid amide hydrolase (FAAH). A number of FAAH inhibitors that increase the levels of OEA and PEA in the brain have been developed, including URB597. In the present report, we examined whether URB597, OEA or PEA injected into wake-related brain areas, such as lateral hypothalamus (LH) or dorsal raphe nuclei (DRN) would promote wakefulness (W) in rats. METHODOLOGY AND PRINCIPAL FINDINGS: Male Wistar rats (250-300 g) were implanted for sleep studies with electrodes to record the electroencephalogram and electromyogram as well as a cannulae aimed either into LH or into DRN. Sleep stages were scored to determine W, slow wave sleep (SWS) and rapid eye movement sleep (REMS). Power spectra bands underly neurophysiological mechanisms of the sleep-wake cycle and provide information about quality rather than quantity of sleep, thus fast Fourier transformation analysis was collected after the pharmacological trials for alpha (for W; α = 8-12 Hz), delta (for SWS; δ = 0.5-4.0 Hz) and theta (for REMS; θ = 6.0-12.0 Hz). Finally, microdialysis samples were collected from a cannula placed into the nucleus accumbens (AcbC) and the levels of dopamine (DA) were determined by HPLC means after the injection of URB597, OEA or PEA. We found that microinjection of compounds (10, 20, 30 µg/1 µL; each) into LH or DRN during the lights-on period increased W and decreased SWS as well as REMS and enhanced DA extracellular levels. CONCLUSIONS: URB597, OEA or PEA promoted waking and enhanced DA if injected into LH or DRN. The wake-promoting effects of these compounds could be linked with the enhancement in levels of DA and indirectly mediated by anandamide.

Effects on sleep and dopamine levels of microdialysis perfusion of cannabidiol into the lateral hypothalamus of rats.

AIMS: The major non-psychoactive component of Cannabis sativa, cannabidiol (CBD), displays a plethora of actions including wakefulness. In the present study, we addressed whether perfusing CBD via microdialysis into lateral hypothalamus (LH) during the lights-on period would modify the sleep-wake cycle of rats as well as the contents of dopamine (DA) collected from nucleus accumbens (AcbC). Additionally, we tested whether perfusion of CBD into LH would block the sleep rebound after a sleep deprivation period. MAIN METHODS: Electroencephalogram and electromyogram electrodes were implanted in rats as well as a guide-cannula aimed to LH or AcbC. CBD perfusion was carried out via cannulae placed into LH whereas contents of DA were collected from AcbC and analyzed using HPLC means. KEY FINDINGS: We found that microdialysis perfusion of CBD (30, 60, or 90 nM) into LH of rat enhances alertness and suppresses sleep. This effect was accompanied with an increase in DA extracellular levels collected from the AcbC. Furthermore, perfusion of CBD into LH after total sleep deprivation prevented the sleep rebound. SIGNIFICANCE: These findings enhance the investigation about the neurobiological properties of CBD on sleep modulation.

Cannabidiol--recent advances.

The aim of this review is to present some of the recent publications on cannabidiol (CBD; 2), a major non-psychoactive constituent of Cannabis, and to give a general overview. Special emphasis is laid on biochemical and pharmacological advances, and on novel mechanisms recently put forward, to shed light on some of the pharmacological effects that can possibly be rationalized through these mechanisms. The plethora of positive pharmacological effects observed with CBD make this compound a highly attractive therapeutic entity.

Cannabidiol, a constituent of Cannabis sativa, modulates sleep in rats.

Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and cannabidiol (CBD) are two major constituents of Cannabis sativa. Delta(9)-THC modulates sleep, but no clear evidence on the role of CBD is available. In order to determine the effects of CBD on sleep, it was administered intracerebroventricular (icv) in a dose of 10 microg/5 microl at the beginning of either the lights-on or the lights-off period. We found that CBD administered during the lights-on period increased wakefulness (W) and decreased rapid eye movement sleep (REMS). No changes on sleep were observed during the dark phase. Icv injections of CBD (10 microg/5microl) induced an enhancement of c-Fos expression in waking-related brain areas such as hypothalamus and dorsal raphe nucleus (DRD). Microdialysis in unanesthetized rats was carried out to characterize the effects of icv administration of CBD (10 microg/5 microl) on extracellular levels of dopamine (DA) within the nucleus accumbens. CBD induced an increase in DA release. Finally, in order to test if the waking properties of CBD could be blocked by the sleep-inducing endocannabinoid anandamide (ANA), animals received ANA (10 microg/2.5 microl, icv) followed 15 min later by CBD (10 microg/2.5 microl). Results showed that the waking properties of CBD were not blocked by ANA. In conclusion, we found that CBD modulates waking via activation of neurons in the hypothalamus and DRD. Both regions are apparently involved in the generation of alertness. Also, CBD increases DA levels as measured by microdialysis and HPLC procedures. Since CBD induces alertness, it might be of therapeutic value in sleep disorders such as excessive somnolence.

Diurnal variation of arachidonoylethanolamine, palmitoylethanolamide and oleoylethanolamide in the brain of the rat.

The diurnal variations of the endocannabinoid arachidonoylethanolamine (anandamide, ANA) as well as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) were detected and quantified in cerebrospinal fluid (CSF), pons, hippocampus, and hypothalamus in the rat over 24 h using HPLC/MS. In CSF, the 3 compounds presented an increase in their concentration during the lights-on period and a remarkable decrease in their values during the lights-off period. In the pons, ANA, PEA and OEA showed the maximum values during the dark phase. On the other hand, we found that in the hippocampus, ANA increased its concentration during the lights-off period and PEA showed the highest peak at the beginning of the same period. OEA concentration showed no diurnal variations in the hippocampus. Finally, in the hypothalamus, ANA rose during the lights-on period whereas PEA and OEA presented the highest concentration at the end of the lights-off period. We postulate that all compounds are likely to be accumulated in parenchyma during the lights-off period (when animal is awake) and then, released into the CSF in order to reach target regions in turn to modulate diverse behaviors, such as feeding and sleep.