S-adenosyl-l-methionine antidepressant-like effects involve activation of 5-HT1A receptors.

S-adenosyl-l-methionine (SAMe), a methyl donor, induces antidepressant effects in preclinical and clinical studies of depression. However, the mechanisms behind these effects have been poorly investigated. Since SAMe is involved in monoamine metabolism, this work aimed at 1) testing the effects induced by systemic treatment with SAMe in mice submitted to the forced swimming test (FST) and tail suspension test (TST); 2) investigating the involvement of serotonergic neurotransmission in the behavioral effects induced by SAMe. To do that, male Swiss mice received systemic injections (1 injection/day, 1 or 7 days) of imipramine (30 mg/kg), L-methionine (400, 800, 1600, and 3200 mg/kg), SAMe (10, 25, 50, 100, and 200 mg/kg), or vehicle (10 ml/kg) and were submitted to the FST or TST, 30 min after the last injection. The effect of SAMe (50 mg/kg) was further investigated in independent groups of male Swiss mice pretreated with p-chlorophenylalanine (PCPA, serotonin synthesis inhibitor, 150 mg/kg daily, 4 days) or with WAY100635 (5-HT1A receptor antagonist, 0.1 mg/kg, 1 injection). One independent group was submitted to the FST and euthanized immediately after for collection of brain samples for neurochemical analyses. Serotonin (5-HT) and noradrenaline (NA) levels were measured in the hippocampus (HPC) and prefrontal cortex (PFC). Furthermore, to investigate if the treatments used could induce any significant exploratory/motor effect which would interfere with the FST results, the animals were also submitted to the open field test (OFT). The administration of imipramine (30 mg/kg), L-methionine (400, 800, 1600, and 3200 mg/kg), and SAMe (10 and 50 mg/kg) reduced the immobility time in the FST, an effect blocked by pretreatment with PCPA and WAY100635. None of the treatments increased the locomotion in the OFT. In conclusion, our results suggest that the antidepressant-like effects induced by SAMe treatment are dependent on serotonin synthesis and 5-HT1A receptor activation.

Effect of two oral formulations of cannabidiol on responses to emotional stimuli in healthy human volunteers: pharmaceutical vehicle matters

Objective: To compare plasma concentrations of cannabidiol (CBD) following oral administration of two formulations of the drug (powder and dissolved in oil), and to evaluate the effects of these distinct formulations on responses to emotional stimuli in healthy human volunteers. Methods: In a randomized, double-blind, placebo-controlled, parallel-group design, 45 healthy male volunteers were randomly assigned to three groups of 15 subjects that received either 150 mg of CBD powder; 150 mg of CBD dissolved in corn oil; or placebo. Blood samples were collected at different times after administration, and a facial emotion recognition task was completed after 150 min. Results: There were no significant differences across groups in the subjective and physiological measures, nor in the facial emotion recognition task. However, groups that received the drug showed statistically significant differences in baseline measures of plasma CBD, with a significantly greater difference in favor of the oil formulation. Conclusion: When administered as a single 150-mg dose, neither formulation of oral CBD altered responses to emotional stimuli in healthy subjects. The oil-based CBD formulation resulted in more rapid achievement of peak plasma level, with an approximate fourfold increase in oral bioavailability.

Increased body sway in phobic patients exposed to images of spiders

Objective: The aim of the present study was to analyze the body sway response in specific phobia (SP) patients and healthy controls while viewing neutral, phobic, and disgusting images. Methods: The participants' heart rate (HR) and skin conductance were also recorded during the procedure. Nineteen patients with arachnophobia and 19 healthy volunteers matched by age, gender, and years of education underwent a postural control test on a stabilometric platform. Results: The platform recorded increased body sway in the SP group when exposed to spider images (SPI). The SP group presented increases in most parameters (SD, velocity, frequency, area, p ≤ 0.05) when viewing pictures of the SPI category. Psychometric measures of subjective anxiety (State-Trait Anxiety Inventory, STAI) and physiological states (HR; skin conductance responses; spontaneous fluctuations in skin conductance) showed increased anxiety (p ≤ 0.05) in the SP group compared to healthy volunteers. High anxiety levels were observed throughout the assessment, including the task of exposure to SPI (p ≤ 0.05). No significant effect or correlation was found between skin conductance and body sway measures (p > 0.05). Conclusions: The results of the postural control test suggest the occurrence of a defensive escape response in SP, in agreement with previous evidence.

Hemopressin as a breakthrough for the cannabinoid field.

Hemopressin (PVNFKFLSH in rats, and PVNFKLLSH in humans and mice), a fragment derived from the α-chain of hemoglobin, was the first peptide described to have type 1 cannabinoid receptor activity. While hemopressin was shown to have inverse agonist/antagonistic activity, extended forms of hemopressin (i.e. RVD-hemopressin, also called pepcan-12) exhibit type 1 and type 2 cannabinoid receptor agonistic/allosteric activity, and recent studies suggest that they can activate intracellular mitochondrial cannabinoid receptors. Therefore, hemopressin and hemopressin-related peptides could have location-specific and biased pharmacological action, which would increase the possibilities for fine-tunning and broadening cannabinoid receptor signal transduction. Consistent with this, hemopressins were shown to play a role in a number of physiological processes including antinociceptive and anti-inflammatory activity, regulation of food intake, learning and memory. The shortest active hemopressin fragment, NFKF, delays the first seizure induced by pilocarpine, and prevents neurodegeneration in an experimental model of autoimmune encephalomyelitis. These functions of hemopressins could be due to engagement of both cannabinoid and non-cannabinoid receptor systems. Self-assembled nanofibrils of hemopressin have pH-sensitive switchable surface-active properties, and show potential as inflammation and cancer targeted drug-delivery systems. Upon disruption of the self-assembled hemopressin nanofibril emulsion, the intrinsic analgesic and anti-inflammatory properties of hemopressin could help bolster the therapeutic effect of anti-inflammatory or anti-cancer formulations. In this article, we briefly review the molecular and behavioral pharmacological properties of hemopressins, and summarize studies on the intricate and unique mode of generation and binding of these peptides to cannabinoid receptors. Thus, the review provides a window into the current status of hemopressins in expanding the repertoire of signaling and activity by the endocannabinoid system, in addition to their new potential for pharmaceutic formulations.

Biological bases for a possible effect of cannabidiol in Parkinson's disease

Current pharmacotherapy of Parkinson's disease (PD) is palliative and unable to modify the progression of neurodegeneration. Treatments that can improve patients' quality of life with fewer side effects are needed, but not yet available. Cannabidiol (CBD), the major non-psychotomimetic constituent of cannabis, has received considerable research attention in the last decade. In this context, we aimed to critically review the literature on potential therapeutic effects of CBD in PD and discuss clinical and preclinical evidence supporting the putative neuroprotective mechanisms of CBD. We searched MEDLINE (via PubMed) for indexed articles published in English from inception to 2019. The following keywords were used: cannabis; cannabidiol and neuroprotection; endocannabinoids and basal ganglia; Parkinson's animal models; Parkinson's history; Parkinson's and cannabidiol. Few studies addressed the biological bases for the purported effects of CBD on PD. Six preclinical studies showed neuroprotective effects, while three targeted the antidyskinetic effects of CBD. Three human studies have tested CBD in patients with PD: an open-label study, a case series, and a randomized controlled trial. These studies reported therapeutic effects of CBD on non-motor symptoms. Additional research is needed to elucidate the potential effectiveness of CBD in PD and the underlying mechanisms involved.

Cannabidiol presents an inverted U-shaped dose-response curve in a simulated public speaking test

Objective: Cannabidiol (CBD), one of the non-psychotomimetic compounds of Cannabis sativa, causes anxiolytic-like effects in animals, with typical bell-shaped dose-response curves. No study, however, has investigated whether increasing doses of this drug would also cause similar curves in humans. The objective of this study was to compare the acute effects of different doses of CBD and placebo in healthy volunteers performing a simulated public speaking test (SPST), a well-tested anxiety-inducing method. Method: A total of 57 healthy male subjects were allocated to receive oral CBD at doses of 150 mg (n=15), 300 mg (n=15), 600 mg (n=12) or placebo (n=15) in a double-blind procedure. During the SPST, subjective ratings on the Visual Analogue Mood Scale (VAMS) and physiological measures (systolic and diastolic blood pressure, heart rate) were obtained at six different time points. Results: Compared to placebo, pretreatment with 300 mg of CBD significantly reduced anxiety during the speech. No significant differences in VAMS scores were observed between groups receiving CBD 150 mg, 600 mg and placebo. Conclusion: Our findings confirm the anxiolytic-like properties of CBD and are consonant with results of animal studies describing bell-shaped dose-response curves. Optimal therapeutic doses of CBD should be rigorously determined so that research findings can be adequately translated into clinical practice.

DMH-CBD, a cannabidiol analog with reduced cytotoxicity, inhibits TNF production by targeting NF-kB activity dependent on A2A receptor.

Cannabidiol (CBD) is a natural compound with psychoactive therapeutic properties well described. Conversely, the immunological effects of CBD are still poorly explored. In this study, the potential anti-inflammatory effects and underlying mechanisms of CBD and its analog Dimethyl-Heptyl-Cannabidiol (DMH-CBD) were investigated using RAW 264.7 macrophages. CBD and DMH-CBD suppressed LPS-induced TNF production and NF-kB activity in a concentration-dependent manner. Both compounds reduced the NF-kB activity in a µM concentration range: CBD (IC50 = 15 µM) and DMH-CBD (IC50 = 38 µM). However, the concentrations of CBD that mediated NF-kB inhibition were similar to those that cause cytotoxicity (LC50 = 58 µM). Differently, DMH-CBD inhibited the NF-kB activation without cytotoxic effects at the same concentrations, although it provokes cytotoxicity at long-term exposure. The inhibitory action of the DMH-CBD on NF-kB activity was not related to the reduction in IkBα degradation or either p65 (NF-kB) translocation to the nucleus, although it decreased p38 MAP kinase phosphorylation. Additionally, 8-(3-Chlorostyryl) caffeine (CSC), an A2A antagonist, reversed the effect of DMH-CBD on NF-kB activity in a concentration-dependent manner. Collectively, our results demonstrated that CBD reduces NF-kB activity at concentrations intimately associated with those that cause cell death, whereas DMH-CBD decreases NF-kB activity at non-toxic concentrations in an A2A receptor dependent-manner.

Chronic cannabidiol exposure promotes functional impairment in sexual behavior and fertility of male mice.

Cannabidiol (CBD) is a potent substance extracted from Cannabis sativa. As it has been suggested that marijuana can affect the reproductive system, we decided to assess the effects of chronic CBD exposure on the male reproductive system in an animal model. 21-day old male Swiss mice received CBD for 34 consecutive days at doses (p.o.) of either 15 or 30 mg/kg, and a control group received sunflower oil. Body weight gain and circulating progesterone concentration did not significantly change in CBD-treated animals. In the sexual behavior analysis, the CBD 15 group presented a delay in performing the first mount and intromission, and a reduced number of mounts and ejaculations. The CBD 30 group showed a 30% reduction in fertility rate and a 23% reduction in the number of litters. Our results indicate that chronic CBD exposure promotes functional impairment of the reproductive system of male Swiss mice.

CD36 Shunts Eicosanoid Metabolism to Repress CD14 Licensed Interleukin-1ß Release and Inflammation.

Interleukin (IL)-1ß is a potential target for treatment of several inflammatory diseases, including envenomation by the scorpion Tityus serrulatus. In this context, bioactive lipids such as prostaglandin (PG)E2 and leukotriene (LT)B4 modulate the production of IL-1ß by innate immune cells. Pattern recognition receptors (PRRs) that perceive T. serrulatus venom (TsV), and orchestrate LTB4, PGE2, and cyclic adenosine monophosphate (cAMP) production to regulate IL-1ß release are unknown. Furthermore, molecular mechanisms driving human cell responses to TsV remain uncharacterized. Here, we identified that both CD14 and CD36 control the synthesis of bioactive lipids, inflammatory cytokines, and mortality mediated by TsV. CD14 induces PGE2/cAMP/IL-1ß release and inflammation. By contrast, CD36 shunts eicosanoid metabolism toward production of LTB4, which represses the PGE2/cAMP/IL-1ß axis and mortality. Of importance, the molecular mechanisms observed in mice strongly correlate with those of human cell responses to TsV. Overall, this study provides major insights into molecular mechanisms connecting CD14 and CD36 with differential eicosanoid metabolism and inflammation mediated by IL-1ß.

The anxiolytic effects of cannabidiol in chronically stressed mice are mediated by the endocannabinoid system: Role of neurogenesis and dendritic remodeling.

Repeated injections of cannabidiol (CBD), the major non-psychotomimetic compound present in the Cannabis sativa plant, attenuate the anxiogenic effects induced by Chronic Unpredictable Stress (CUS). The specific mechanisms remain to be fully understood but seem to involve adult hippocampal neurogenesis and recruitment of endocannabinoids. Here we investigated for the first time if the behavioral and pro-neurogenic effects of CBD administered concomitant the CUS procedure (14 days) are mediated by CB1, CB2 or 5HT1A receptors, as well as CBD effects on dendritic remodeling and on intracellular/synaptic signaling (fatty acid amide hydrolase - FAAH, Akt, GSK3ß and the synaptic proteins Synapsin Ia/b, mGluR1 and PSD95). After 14 days, CBD injections (30 mg/kg) induced anxiolytic responses in stressed animals in the elevated plus-maze and novelty suppressed feeding tests, that were blocked by pre-treatment with a CB1 (AM251, 0.3 mg/kg) or CB2 (AM630, 0.3 mg/kg), but not by a 5HT1A (WAY100635, 0.05 mg/kg) receptor antagonist. Golgi staining and immunofluorescence revealed that these effects were associated with an increase in hippocampal neurogenesis and spine density in the dentate gyrus of the hippocampus. AM251 and AM630 abolished the effects of CBD on spines density. However, AM630 was more effective in attenuating the pro-neurogenic effects of CBD. CBD decreased FAAH and increased p-GSK3ß expression in stressed animals, which was also attenuated by AM630. These results indicate that CBD prevents the behavioral effects caused by CUS probably due to a facilitation of endocannabinoid neurotransmission and consequent CB1/CB2 receptors activation, which could recruit intracellular/synaptic proteins involved in neurogenesis and dendritic remodeling.

A novel peptide that improves metabolic parameters without adverse central nervous system effects.

Intracellular peptides generated by limited proteolysis are likely to function inside and outside cells and could represent new possibilities for drug development. Here, we used several conformational-sensitive antibodies targeting G-protein coupled receptors to screen for novel pharmacological active peptides. We find that one of these peptides, DITADDEPLT activates cannabinoid type 1 receptors. Single amino acid modifications identified a novel peptide, DIIADDEPLT (Pep19), with slightly better inverse agonist activity at cannabinoid type 1 receptors. Pep19 induced uncoupling protein 1 expression in both white adipose tissue and 3T3-L1 differentiated adipocytes; in the latter, Pep19 activates pERK1/2 and AKT signaling pathways. Uncoupling protein 1 expression induced by Pep19 in 3T3-L1 differentiated adipocytes is blocked by AM251, a cannabinoid type 1 receptors antagonist. Oral administration of Pep19 into diet-induced obese Wistar rats significantly reduces adiposity index, whole body weight, glucose, triacylglycerol, cholesterol and blood pressure, without altering heart rate; changes in the number and size of adipocytes were also observed. Pep19 has no central nervous system effects as suggested by the lack of brain c-Fos expression, cell toxicity, induction of the cannabinoid tetrad, depressive- and anxiety-like behaviors. Therefore, Pep19 has several advantages over previously identified peripherally active cannabinoid compounds, and could have clinical applications.

Cannabidiol attenuates haloperidol-induced catalepsy and c-Fos protein expression in the dorsolateral striatum via 5-HT1A receptors in mice.

Cannabidiol (CBD) is a major non-psychoactive compound from Cannabis sativa plant. Given that CBD reduces psychotic symptoms without inducing extrapyramidal motor side-effects in animal models and schizophrenia patients, it has been proposed to act as an atypical antipsychotic. In addition, CBD reduced catalepsy induced by drugs with distinct pharmacological mechanisms, including the typical antipsychotic haloperidol. To further investigate this latter effect, we tested whether CBD (15-60mg/kg) would attenuate the catalepsy and c-Fos protein expression in the dorsal striatum induced by haloperidol (0.6mg/kg). We also evaluated if these effects occur through the facilitation of 5-HT1A receptor-mediated neurotransmission. For this, male Swiss mice were treated with CBD and haloperidol systemically and then subjected to the catalepsy test. Independent groups of animals were also treated with the 5-HT1A receptor antagonist WAY100635 (0.1mg/kg). As expected, haloperidol induced catalepsy throughout the experiments, an effect that was prevented by systemic CBD treatment 30min before haloperidol administration. Also, CBD, administered 2.5h after haloperidol, reversed haloperidol-induced catalepsy. Haloperidol also increased c-Fos protein expression in the dorsolateral striatum, an effect attenuated by previous CBD administration. CBD effects on catalepsy and c-Fos protein expression induced by haloperidol were blocked by the 5-HT1A receptor antagonist. We also evaluated the effects of CBD (60nmol) injection into the dorsal striatum on haloperidol-induced catalepsy. Similar to systemic administration, this treatment reduced catalepsy induced by haloperidol. Altogether, these results suggest that CBD acts in the dorsal striatum to improve haloperidol-induced catalepsy via postsynaptic 5-HT1A receptors.

Effects of minocycline add-on treatment on brain morphometry and cerebral perfusion in recent-onset schizophrenia.

Increasing evidence suggests that the tetracycline antibiotic minocycline has neuroprotective effects and is a potential treatment for schizophrenia. However, the mechanisms of action of minocycline in the CNS remain elusive. The aim of this study was to investigate the effects of minocycline on brain morphology and cerebral perfusion in patients with recent-onset schizophrenia after 12months of a randomized double-blind, placebo-controlled clinical trial of minocycline add-on treatment. This study included 24 outpatients with recent-onset schizophrenia randomized for 12months of adjuvant treatment with minocycline (200mg/d) or placebo. MRI (1.5T) and [(99m)Tc]-ECD SPECT brain scans were performed at the end of the 12-month of trial. Between-condition comparisons of SPECT and MRI brain images were performed using statistical parametric mapping and analyzed by voxel-based morphometry (VBM). Minocycline adjuvant treatment significantly reduced positive and negative symptoms when compared with placebo. The VBM analysis of MRI scans showed that the patients in the placebo group had significant lower gray matter volumes in the midposterior cingulate cortex and in the precentral gyrus in comparison with the patients in the minocycline group. In addition, a decreased ECD uptake in the minocycline condition was observed in fronto-temporal areas. These results suggest that minocycline may protect against gray matter loss and modulate fronto-temporal areas involved in the pathophysiology of schizophrenia. Furthermore, minocycline add-on treatment may be a potential treatment in the early stages of schizophrenia and may ameliorate clinical deterioration and brain alterations observed in this period.

Involvement of TRPV1 channels in the periaqueductal grey on the modulation of innate fear responses.

OBJECTIVES: The transient receptor potential vanilloid type-1 channel (TRPV1) is expressed in the midbrain periaqueductal grey (PAG), a region of the brain related to aversive responses. TRPV1 antagonism in the dorsolateral PAG (dlPAG) induces anxiolytic-like effects in models based on conflict situations. No study, however, has investigated whether these receptors could contribute to fear responses to proximal threat. Thus, we tested the hypothesis that TRPV1 in the PAG could mediate fear response in rats exposed to a predator. METHODS: We verified whether exposure to a live cat (a natural predator) would activate TRPV1-expressing neurons in the PAG. Double-staining immunohistochemistry was used as a technique to detect c-Fos, a marker of neuronal activation, and TRPV1 expression. We also investigated whether intra-dlPAG injections of the TRPV1 antagonist, capsazepine (CPZ), would attenuate the behavioural consequences of predator exposure. RESULTS: Exposure to a cat increased c-Fos expression in TRPV1-positive neurons, mainly in the dorsal columns of the PAG, suggesting that TRPV1-expressing neurons are activated by threatening stimuli. Accordingly, local injection of CPZ inhibited the fear responses. CONCLUSION: These data support the hypothesis that TRPV1 channels mediate fear reactions in the dlPAG. This may have an implication for the development of TRPV1-antagonists as potential drugs for the treatment of certain psychiatric disorders.

Cannabidiol attenuates sensorimotor gating disruption and molecular changes induced by chronic antagonism of NMDA receptors in mice.

BACKGROUND: Preclinical and clinical data suggest that cannabidiol (CBD), a major non-psychotomimetic compound from Cannabis sativa, induces antipsychotic-like effects. However, the antipsychotic properties of repeated CBD treatment have been poorly investigated. Behavioral changes induced by repeated treatment with glutamate N-methyl-D-aspartate receptor (NMDAR) antagonists have been proposed as an animal model of schizophrenia-like signs. In the present study, we evaluated if repeated treatment with CBD would attenuate the behavioral and molecular modifications induced by chronic administration of one of these antagonists, MK-801. METHODS: Male C57BL/6J mice received daily i.p. injections of MK-801 (0.1, 0.5, or 1mg/kg) for 14, 21, or 28 days. Twenty-four hours after the last injection, animals were submitted to the prepulse inhibition (PPI) test. After that, we investigated if repeated treatment with CBD (15, 30, and 60mg/kg) would attenuate the PPI impairment induced by chronic treatment with MK-801 (1mg/kg; 28 days). CBD treatment began on the 6th day after the start of MK-801 administration and continued until the end of the treatment. Immediately after the PPI, the mice brains were removed and processed to evaluate the molecular changes. We measured changes in FosB/ΔFosB and parvalbumin (PV) expression, a marker of neuronal activity and a calcium-binding protein expressed in a subclass of GABAergic interneurons, respectively. Changes in mRNA expression of the NMDAR GluN1 subunit gene (GRN1) were also evaluated. CBD effects were compared to those induced by the atypical antipsychotic clozapine. RESULTS: MK-801 administration at the dose of 1mg/kg for 28 days impaired PPI responses. Chronic treatment with CBD (30 and 60mg/kg) attenuated PPI impairment. MK-801 treatment increased FosB/ΔFosB expression and decreased PV expression in the medial prefrontal cortex. A decreased mRNA level of GRN1 in the hippocampus was also observed. All the molecular changes were attenuated by CBD. CBD by itself did not induce any effect. Moreover, CBD effects were similar to those induced by repeated clozapine treatment. CONCLUSIONS: These results indicate that repeated treatment with CBD, similar to clozapine, reverses the psychotomimetic-like effects and attenuates molecular changes observed after chronic administration of an NMDAR antagonist. These data support the view that CBD may have antipsychotic properties.

Animal models of anxiety disorders and stress

Anxiety and stress-related disorders are severe psychiatric conditions that affect performance in daily tasks and represent a high cost to public health. The initial observation of Charles Darwin that animals and human beings share similar characteristics in the expression of emotion raise the possibility of studying the mechanisms of psychiatric disorders in other mammals (mainly rodents). The development of animal models of anxiety and stress has helped to identify the pharmacological mechanisms and potential clinical effects of several drugs. Animal models of anxiety are based on conflict situations that can generate opposite motivational states induced by approach-avoidance situations. The present review revisited the main rodent models of anxiety and stress responses used worldwide. Here we defined as “ethological” the tests that assess unlearned/unpunished responses (such as the elevated plus maze, light-dark box, and open field), whereas models that involve learned/punished responses are referred to as “conditioned operant conflict tests” (such as the Vogel conflict test). We also discussed models that involve mainly classical conditioning tests (fear conditioning). Finally, we addressed the main protocols used to induce stress responses in rodents, including psychosocial (social defeat and neonatal isolation stress), physical (restraint stress), and chronic unpredictable stress.

Cannabidiol inhibits the hyperphagia induced by cannabinoid-1 or serotonin-1A receptor agonists.

Δ9-THC is a component of Cannabis sativa that increases food intake in animals and humans, an effect prevented by selective CB1 receptor antagonists. Cannabidiol (CBD) is another constituent of this plant that promotes several opposite neuropharmacological effects compared to Δ9-THC. CBD mechanisms of action are still not clear, but under specific experimental conditions it can antagonize the effects of cannabinoid agonists, block the reuptake of anandamide and act as an agonist of 5-HT1A receptors. Since both the cannabinoid and serotoninergic systems have been implicated in food intake control, the aim of the present work was to investigate the effects caused by CBD on hyperphagia induced by agonists of CB1 or 5-HT1A receptors. Fed or fasted Wistar rats received intraperitoneal (i.p.) injections of CBD (1, 10 and 20 mg/kg) and food intake was measured 30 min later for 1 h. Moreover, additional fed or fasted groups received, after pretreatment with CBD (20 mg/kg) or vehicle, i.p. administration of vehicle, a CB1 receptor agonist WIN55,212-2 (2 mg/kg) or a 5-HT1A receptor agonist 8-OH-DPAT (1 mg/kg) and were submitted to the food intake test for 1 h. CBD by itself did not change food intake in fed or fasted rats. However, it prevented the hyperphagic effects induced by WIN55,212-2 or 8-OH-DPAT. These results show that CBD can interfere with food intake changes induced by a CB1 or 5-HT1A receptor agonist, suggesting that its role as a possible food intake regulator should be further investigate.

Cannabidiol decreases bone resorption by inhibiting RANK/RANKL expression and pro-inflammatory cytokines during experimental periodontitis in rats.

Cannabidiol (CBD) is a cannabinoid component from Cannabis sativa that does not induce psychotomimetic effects and possess anti-inflammatory properties. In the present study we tested the effects of CBD in a periodontitis experimental model in rats. We also investigated possible mechanisms underlying these effects. Periodontal disease was induced by a ligature placed around the mandible first molars of each animal. Male Wistar rats were divided into 3 groups: control animals; ligature-induced animals treated with vehicle and ligature-induced animals treated with CBD (5 mg/kg, daily). Thirty days after the induction of periodontal disease the animals were sacrificed and mandibles and gingival tissues removed for further analysis. Morphometrical analysis of alveolar bone loss demonstrated that CBD-treated animals presented a decreased alveolar bone loss and a lower expression of the activator of nuclear factor-kappaB ligand RANKL/RANK. Moreover, gingival tissues from the CBD-treated group showed decreased neutrophil migration (MPO assay) associated with lower interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha production. These results indicate that CBD may be useful to control bone resorption during progression of experimental periodontitis in rats.

Antidepressant-like effects of N-acetyl-L-cysteine in rats.

Oxidative stress disturbances have been reported in depressed patients and in animals submitted to stress. Recent evidence suggests that antidepressants may have antioxidant properties. However, the therapeutic potential of antioxidants as antidepressant drugs has not been systematically investigated. Therefore, this study tested the hypothesis that N-acetyl-L-cysteine (NAC), a cysteine prodrug with powerful antioxidant activity, would possess antidepressant-like properties in the forced swimming test. Male Wistar rats were subjected to 15 min of forced swimming and immediately afterward, 5, and 23 h later received intraperitoneal injections of NAC (5, 15, 50, 150, and 250 mg/kg), imipramine, (15 mg/kg) or vehicle. One hour later they were submitted to the 5 min test swimming session, where immobility time was recorded. Independent groups of animals received the same treatments and their exploratory activity was measured in an open arena for 5 min. NAC (at the doses of 15, 50, and 150 mg/kg) and imipramine induced a significant decrease in immobility time without changing exploratory behavior measured in an open arena. These results suggest that antioxidants such as NAC may have antidepressant effects.