Cannabinoid Receptor Type Research Articles

Uso medicinal da Cannabis sativa na oncologia veterinária

The growing use of Cannabis sativa for medicinal purposes, both in human and veterinary medicine, in various treatments, including oncology, has been gaining prominence due to the potentially beneficial therapeutic properties of its compounds. The animal body has an endocannabinoid system (ECS) that regulates several physiological functions and is composed of phytocannabinoids that activate cannabinoid receptors type 1 (CB1) and type 2 (CB2), which bind to endogenous cannabinoids (AEA and 2-AG ) and exogenous (THC and CBD). The objective of this review was to research scientific articles on the role of the endocannabinoid system in cancer patients, in order to evaluate the feasibility of using cannabinoids in these patients, in search of improving quality of life.

A Proteomic Approach Identified TFEB as a Key Player in the Protective Action of Novel CB2R Bitopic Ligand FD22a against the Deleterious Effects Induced by β-Amyloid in Glial Cells.

Neurodegenerative diseases (NDDs) are progressive multifactorial disorders of the nervous system sharing common pathogenic features, including intracellular misfolded protein aggregation, mitochondrial deficit, and inflammation. Taking into consideration the multifaceted nature of NDDs, development of multitarget-directed ligands (MTDLs) has evolved as an attractive therapeutic strategy. Compounds that target the cannabinoid receptor type II (CB2R) are rapidly emerging as novel effective MTDLs against common NDDs, such as Alzheimer's disease (AD). We recently developed the first CB2R bitopic/dualsteric ligand, namely FD22a, which revealed the ability to induce neuroprotection with fewer side effects. To explore the potential of FD22a as a multitarget drug for the treatment of NDDs, we investigated here its ability to prevent the toxic effect of β-amyloid (Aβ25-35 peptide) on human cellular models of neurodegeneration, such as microglia (HMC3) and glioblastoma (U87-MG) cell lines. Our results displayed that FD22a efficiently prevented Aβ25-35 cytotoxic and proinflammatory effects in both cell lines and counteracted β-amyloid-induced depression of autophagy in U87-MG cells. Notably, a quantitative proteomic analysis of U87-MG cells revealed that FD22a was able to potently stimulate the autophagy-lysosomal pathway (ALP) by activating its master transcriptional regulator TFEB, ultimately increasing the potential of this novel CB2R bitopic/dualsteric ligand as a multitarget drug for the treatment of NDDs.

Cannabidiol ameliorates PTSD-like symptoms by inhibiting neuroinflammation through its action on CB2 receptors in the brain of male mice

Post-traumatic stress disorder (PTSD) is a debilitating mental health disease related to traumatic experience, and its treatment outcomes are unsatisfactory. Accumulating research has indicated that cannabidiol (CBD) exhibits anti-PTSD effects, however, the underlying mechanism of CBD remains inadequately investigated. Although many studies pertaining to PTSD have primarily focused on aberrations in neuronal functioning, the present study aimed to elucidate the involvement and functionality of microglia/macrophages in PTSD while also investigated the modulatory effects of CBD on neuroinflammation associated with this condition. We constructed a modified single-prolonged stress (SPS) mice PTSD model and verified the PTSD-related behaviors by various behavioral tests (contextual freezing test, elevated plus maze test, tail suspension test and novel object recognition test). We observed a significant upregulation of Iba-1 and alteration of microglial/macrophage morphology within the prefrontal cortex and hippocampus, but not the amygdala, two weeks after the PTSD-related stress, suggesting a persistent neuroinflammatory phenotype in the PTSD-modeled group. CBD (10 mg/kg, i.p.) inhibited all PTSD-related behaviors and reversed the alterations in both microglial/macrophage quantity and morphology when administered prior to behavioral assessments. We further found increased pro-inflammatory factors, decreased PSD95 expression, and impaired synaptic density in the hippocampus of the modeled group, all of which were also restored by CBD treatment. CBD dramatically increased the level of anandamide, one of the endocannabinoids, and cannabinoid type 2 receptors (CB2Rs) transcripts in the hippocampus compared with PTSD-modeled group. Importantly, we discovered the expression of CB2Rs mRNA in Arg-1-positive cells in vivo and found that the behavioral effects of CBD were diminished by CB2Rs antagonist AM630 (1 mg/kg, i.p.) and both the behavioral and molecular effects of CBD were abolished in CB2Rs knockout mice. These findings suggest that CBD would alleviate PTSD-like behaviors in mice by suppressing PTSD-related neuroinflammation and upregulation and activation of CB2Rs may serve as one of the underlying mechanisms for this therapeutic effect. The present study offers innovative experimental evidence supporting the utilization of CBD in PTSD treatment from the perspective of its regulation of neuroinflammation, and paves the way for leveraging the endocannabinoid system to regulate neuroinflammation as a potential therapeutic approach for psychiatric disorders.

Weight Loss and Therapeutic Metabolic Effects of Tetrahydrocannabivarin (THCV)-Infused Mucoadhesive Strips

Objective: Metabolic syndrome is due to dysregulation that starts with fat accumulation, causing inflammatory response, insulin resistance, dyslipidemia, hypertension, and fatty liver disease. The endocannabinoid system, via cannabinoid receptor type 1 (CB1), has been shown to be involved with energy homeostasis and regulation of appetitive behavior via activity in the hypothalamus, limbic forebrain and amygdala and in the peripheral tissues including adipose, liver and muscle. Therefore, two phytocannabinoids, tetrahydrocannabivarin (THCV), a CB1 neutral antagonist, and cannabidiol (CBD), a negative allosteric modulator of CB1, are expected to have therapeutic metabolic benefits, including weight loss. Method: A placebo-controlled study was conducted on 44 subjects (31 females and 13 males) with an average age of 51.75. The study evaluated the efficacy of two different doses of THCV and CBD (8 mg THCV/10 mg CBD in the lower dose and 16 mg THCV/20 mg CBD in the higher dose), taken once daily for 90 days via mucoadhesive oral strips, for weight loss and improvement of certain metabolic markers. Results: Use of the THCV/CBD strip was associated with statistically significant weight loss, decreases in abdominal girth, systolic blood pressure, and total and LDL cholesterol. The study was limited by small sample sizes in both the high dose and placebo groups. Conclusions: The 16 mg/20 mg daily dose was superior for weight loss compared to the 8 mg/10 mg daily dose; both sets of results differed from placebo in a way that was statistically significant. The results of this study were congruent with the prior unpublished studies of a hemp extract containing significant percentages of THCV, CBDV and CBD.

Retraction: Improved cognition impairment by activating cannabinoid receptor type 2: Modulating CREB/BDNF expression and impeding TLR-4/NFκBp65/M1 microglia signaling pathway in D-galactose-injected ovariectomized rats.

Retraction: Improved cognition impairment by activating cannabinoid receptor type 2: Modulating CREB/BDNF expression and impeding TLR-4/NFκBp65/M1 microglia signaling pathway in D-galactose-injected ovariectomized rats.

Shared genetic architecture highlights the bidirectional association between major depressive disorder and fracture risk

BackgroundThere is limited evidence suggesting that osteoporosis might exacerbate depressive symptoms, while more studies demonstrate that depression negatively affects bone density and increases fracture risk.AimsTo explore the relationship between major...

Involvement of heart-gut axis in endocannabinoid CB1R signaling following alcohol binge

Introduction: Binge alcohol drinking is linked to an increasing number of emergency room visits and rising healthcare costs. We have recently shown that binge alcohol drinking is associated with the activation of cannabinoid receptor type-1 (CB1R) signaling, aggravating binge alcohol-induced cardiovascular dysfunction. The endogenous CB1R agonist, anandamide (AEA), can form in response to various stimuli including increased levels of circulating endotoxins derived from intestinal Gram-negative bacteria. Besides, increased levels of serum endotoxins can also provoke the activation of innate immune cells. However, it is still unclear if how AEA is formed in the cardiovascular system. Here, we studied the effect of intestinal Gram-negative bacteria-derived endotoxins on myocardial CB1R activation and aimed to identify the cellular source of AEA after alcohol binge. Methods: 8-12 week old C57BL/6J mice were orally administered a single ethanol binge at a dose of 5g/kg body weight, with or without prior treatment with non-absorbable antibiotics. Circulating endotoxins were assessed following alcohol binge. Intestinal-barrier permeability was assayed by using FITC-Dextran administration. Myocardial tissue endocannabinoid levels were measured by LC/MS. Immunostaining approaches were applied to determine the rate of oxidative stress in the myocardium. Left ventricle performance was assessed by using a pressure-volume catheterization approach. Tissue perfusion was also evaluated by laser speckle contrast imaging. Results: Alcohol gavage was associated with a time-dependent increase of serum endotoxins peaking 3h after intoxication. Selective intestinal decontamination significantly improved the gut barrier function following alcohol gavage which was concomitant with the decreased myocardial oxidative stress. Simultaneously, reduced levels of myocardial AEA and cardiovascular performance improvement were observed. Conclusion: Our findings underscore the potential role of Gram-negative flora derived substances in the modulation of cardiovascular endocannabinoid AEA levels following alcohol binge drinking, impacting cardiac function and oxidative stress. Supported by Intramural Research Program of NIH/NIAAA; R00AA028300, LSUHSC start-up funds. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effects of CB1 receptor negative allosteric modulator Org27569 on oxycodone withdrawal symptoms in mice

Rationale/ObjectivesTargeting cannabinoid receptor type 1 (CB1R) has shown promise for treating opioid withdrawal symptoms. This study aimed to investigate the efficacy of a specific CB1R negative allosteric modulator (NAM), Org27569, in reducing both naloxone-precipitated and protracted withdrawal symptoms in oxycodone-dependent mice.MethodsMice received escalating doses of oxycodone (9–33 mg/kg IP) or saline twice daily for 9 days, followed by a final dose of oxycodone (33 mg/kg) or saline in the morning of day 9. In one cohort, the impact of Org27569 (3, 10, and 30 mg/kg) on naloxone (10 mg/kg IP) precipitated withdrawal symptoms was assessed. In another cohort, Org27569 (3 mg/kg) effects on the acquisition of conditioned place aversion to naloxone (0.6 mg/kg) precipitated opioid withdrawal, on behaviour following a 7–9-day abstinence period, and on naloxone (0.6 mg/kg) precipitated withdrawal-induced escape behaviour in a novel assay were assessed.ResultsAlthough Org27569 decreased opioid withdrawal-induced jumping at doses of 10 and 30 mg/kg, these effects were confounded by reduced locomotion. At all doses tested, Org27569 had a modest inhibitory effect on gastrointestinal motility. At the lower dose of 3 mg/kg, which was not confounded by locomotor effects, Org27569 did not impact naloxone-precipitated withdrawal-induced jumping, acquisition of oxycodone withdrawal-induced conditioned place aversion, or naloxone-precipitated withdrawal-induced escape behaviour in a novel assay. A clear protracted opioid withdrawal phenotype was not observed in assays of anxiety-like or social behaviour.ConclusionsOrg27569 effects on negative affective-like symptoms were confounded by locomotor effects and effects on gastrointestinal motility were not opioid withdrawal specific. Further studies are needed in a model that produces a more pronounced protracted withdrawal syndrome.

The CB1 negative allosteric modulator PSNCBAM-1 reduces ethanol self-administration via a nonspecific hypophagic effect

Alcohol use disorder (AUD) affects >15 million people in the United States. Current pharmacotherapeutic treatments for AUD are only modestly effective, necessitating the identification of new targets for medications development. The cannabinoid receptor type 1 (CB1) has been a target of interest for the development of medications for substance use disorders and other compulsive disorders. However, CB1 antagonists/inverse agonists (e.g., rimonabant) have severe side effects that limit their clinical utility, including anxiety, depression, and suicide. Recent development of CB1 negative allosteric modulators (NAMs), including PSNCBAM-1, may provide an alternative mechanism of attenuating CB1 signaling with reduced side effects. PSNCBAM-1 has not yet been evaluated for effects in models of AUD. In this study, we investigated the effects of the CB1 NAM, PSNCBAM-1, in rodent models of AUD using adult male mice. PSNCBAM-1 dose-dependently attenuated oral ethanol self-administration (8 % w/v ethanol in water), significantly reducing ethanol rewards at a dose of 30 mg/kg, but not at 10 or 18 mg/kg. PSNCBAM-1 also dose-dependently attenuated palatable food self-administration (diluted vanilla Ensure), significantly reducing food rewards at 18 and 30 mg/kg PSNCBAM-1. PSNCBAM-1 did not affect conditioned place preference for 2 g/kg ethanol. These results suggest PSNCBAM-1 reduces ethanol-taking behavior via a nonspecific hypophagic effect and does not reduce the rewarding effects of ethanol.

Discovery and development of macrocyclic peptide modulators of the cannabinoid 2 receptor

The cannabinoid type 2 receptor (CB2R), a G protein-coupled receptor, is an important regulator of immune cell function and a promising target to treat chronic inflammation and fibrosis. While CB2R is typically targeted by small molecules, including endo-, phyto-, and synthetic cannabinoids, peptides-owing to their size-may offer a different interaction space to facilitate differential interactions with the receptor. Here, we explore plant-derived cyclic cystine-knot peptides as ligands of the CB2R. Cyclotides are known for their exceptional biochemical stability. Recently, they gained attention as G protein-coupled receptor modulators and as templates for designing peptide ligands with improved pharmacokinetic properties over linear peptides. Cyclotide-based ligands for CB2R were profiled based on a peptide-enriched extract library comprising nine plants. Employing pharmacology-guided fractionation and peptidomics, we identified the cyclotide vodo-C1 from sweet violet (Viola odorata) as a full agonist of CB2R with an affinity (Ki) of 1μM and a potency (EC50) of 8μM. Leveraging deep learning networks, we verified the structural topology of vodo-C1 and modeled its molecular volume in comparison to the CB2R ligand binding pocket. In a fragment-based approach, we designed and characterized vodo-C1-based bicyclic peptides (vBCL1-4), aiming to reduce size and improve potency. Opposite to vodo-C1, the vBCL peptides lacked the ability to activate the receptor but acted as negative allosteric modulators or neutral antagonists of CB2R. This study introduces a macrocyclic peptide phytocannabinoid, which served as a template for the development of synthetic CB2R peptide modulators. These findings offer opportunities for future peptide-based probe and drug development at cannabinoid receptors.

CB1 receptor mediates anesthetic drug ketamine‑induced neuroprotection against glutamate in HT22 cells.

The anesthetic drug, ketamine (KTM) has been shown to induce therapeutic effects against major depressive disorder (MDD), however the related underlying mechanisms remain unclear. In the present study, HT22 neuronal cells were treated with glutamate to imitate oxidative stress injury in MDD, and it was hypothesized that the cannabinoid type 1 (CB1) receptor mediates KTM-induced neuroprotection via ameliorating mitochondrial function in glutamate-treated neuronal cells. Compared with the control, glutamate decreased cell viability and intracellular antioxidants, including glutathione (GSH), catalase and superoxide dismutase 2 levels, and inhibited mitochondrial function simultaneously. Moreover, glutamate increased lactate dehydrogenase release, cellular apoptosis level, cleaved caspase-3 expression and intracellular oxidants, such as reactive oxygen species, oxidized GSH and mitochondrial superoxide in the cells. The presence of KTM, however, significantly decreased the glutamate-induced oxidative stress injury, ameliorated the antioxidant/oxidant levels in the cells, enhanced mitochondrial function and upregulated CB1 receptor expression (P<0.05). Co-administration of the CB1 receptor antagonist AM251 markedly abolished the KTM-induced cytoprotective effects and ameliorations of antioxidant/oxidant levels and mitochondrial function, and also reversed CB1 upregulation (P<0.05). These observations indicated that KTM decreases the oxidative stress injury caused by glutamate in HT22 neuronal cells, and the neuroprotective effects may be mediated by the CB1 receptor.

Discriminative stimulus properties of Cannabis sativa terpenes in rats.

Cannabis is a pharmacologically complex plant consisting of hundreds of potentially active compounds. One class of compounds present in cannabis that has received little attention are terpenes. Traditionally thought to impart aroma and flavor to cannabis, it has become increasingly recognized that terpenes might exert therapeutic effects themselves. Several recent reports have also indicated terpenes might behave as cannabinoid type 1 (CB1) receptor agonists. This study aimed to investigate whether several terpenes present in cannabis produce discriminative stimulus effects similar to or enhance the effects of Δ 9 -tetrahydrocannabinol (THC). Subsequent experiments explored other potential cannabimimetic effects of these terpenes. Rats were trained to discriminate THC from vehicle while responding under a fixed-ratio 10 schedule of food presentation. Substitution testing was performed with the CB receptor agonist JWH-018 and the terpenes linalool, limonene, γ-terpinene and α-humulene alone. Terpenes were also studied in combination with THC. Finally, THC and terpenes were tested in the tetrad assay to screen for CB1-receptor agonist-like effects. THC and JWH-018 dose-dependently produced responding on the THC-paired lever. When administered alone, none of the terpenes produced responding predominantly on the THC-paired lever. When administered in combination with THC, none of the terpenes enhanced the potency of THC, and in the case of α-humulene, decreased the potency of THC to produce responding on the THC-paired lever. While THC produced effects in all four tetrad components, none of the terpenes produced effects in all four components. Therefore, the terpenes examined in this report do not have effects consistent with CB1 receptor agonist properties in the brain.

Cannabidiol attenuates seizure susceptibility and behavioural deficits in adult CDKL5R59X knock-in mice.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is caused by a loss-of-function mutation in CDKL5 gene, encoding a serine-threonine kinase highly expressed in the brain. CDD manifests with early-onset epilepsy, autism, motor impairment and severe intellectual disability. While there are no known treatments for CDD, the use of cannabidiol has recently been introduced into clinical practice for neurodevelopmental disorders. Given the increased clinical utilization of cannabidiol, we examined its efficacy in the CDKL5R59X knock-in (R59X) mice, a CDD model based on a human mutation that exhibits both lifelong seizure susceptibility and behavioural deficits. We found that cannabidiol pre-treatment rescued the increased seizure susceptibility in response to the chemoconvulsant pentylenetetrazol (PTZ), attenuated working memory and long-term memory impairments, and rescued social deficits in adult R59X mice. To elucidate a potential mechanism, we compared the developmental hippocampal and cortical expression of common endocannabinoid (eCB) targets in R59X mice and their wild-type littermates, including cannabinoid type 1 receptor (CB1R), transient receptor potential vanilloid type 1 (TRPV1) and 2 (TRPV2), G-coupled protein receptor 55 (GPR55) and adenosine receptor 1 (A1R). Many of these eCB targets were developmentally regulated in both R59X and wild-type mice. In addition, adult R59X mice demonstrated significantly decreased expression of CB1R and TRPV1 in the hippocampus, and TRPV2 in the cortex, while TRPV1 was increased in the cortex. These findings support the potential for dysregulation of eCB signalling as a plausible mechanism and therapeutic target in CDD, given the efficacy of cannabidiol to attenuate hyperexcitability and behavioural deficits in this disorder.

Cannabinoids regulate an insula circuit controlling water intake

The insular cortex, or insula, is a large brain region involved in the detection of thirst and the regulation of water intake. However, our understanding of the topographical, circuit, and molecular mechanisms for controlling water intake within the insula remains parcellated. We found that type-1 cannabinoid (CB1) receptors in the insular cortex cells participate in the regulation of water intake and deconstructed the circuit mechanisms of this control. Topographically, we revealed that the activity of excitatory neurons in both the anterior insula (aIC) and posterior insula (pIC) increases in response to water intake, yet only the specific removal of CB1 receptors in the pIC decreases water intake. Interestingly, we found that CB1 receptors are highly expressed in insula projections to the basolateral amygdala (BLA), while undetectable in the neighboring central part of the amygdala. Thus, we recorded the neurons of the aIC or pIC targeting the BLA (aIC-BLA and pIC-BLA) and found that they decreased their activity upon water drinking. Additionally, chemogenetic activation of pIC-BLA projection neurons decreased water intake. Finally, we uncovered CB1-dependent short-term synaptic plasticity (depolarization-induced suppression of excitation [DSE]) selectively in pIC-BLA, compared with aIC-BLA synapses. Altogether, our results support a model where CB1 receptor signaling promotes water intake by inhibiting the pIC-BLA pathway, thereby contributing to the fine top-down control of thirst responses.

P2X7 receptor-dependent increase in endocannabinoid 2-arachidonoyl glycerol production by neuronal cells in culture: Dynamics and mechanism.

Neurotransmission and neuroinflammation are controlled by local increases in both extracellular ATP and the endocannabinoid 2-arachidonoyl glycerol (2-AG). While it is known that extracellular ATP stimulates 2-AG production in cells in culture, the dynamics and molecular mechanisms that underlie this response remain poorly understood. Detection of real-time changes in eCB levels with the genetically encoded sensor, GRABeCB2.0, can address this shortfall. 2-AG and arachidonoylethanolamide (AEA) levels in Neuro2a (N2a) cells were measured by LC-MS, and GRABeCB2.0 fluorescence changes were detected using live-cell confocal microscopy and a 96-well fluorescence plate reader. 2-AG and AEA increased GRABeCB2.0 fluorescence in N2a cells with EC50 values of 81 and 58 nM, respectively; both responses were reduced by the cannabinoid receptor type 1 (CB1R) antagonist SR141617 and absent in cells expressing the mutant-GRABeCB2.0. ATP increased only 2-AG levels in N2a cells, as measured by LC-MS, and induced a transient increase in the GRABeCB2.0 signal within minutes primarily via activation of P2X7 receptors (P2X7R). This response was dependent on diacylglycerol lipase β activity, partially dependent on extracellular calcium and phospholipase C activity, but not controlled by the 2-AG hydrolysing enzyme, α/β-hydrolase domain containing 6 (ABHD6). Considering that P2X7R activation increases 2-AG levels within minutes, our results show how these molecular components are mechanistically linked. The specific molecular components in these signalling systems represent potential therapeutic targets for the treatment of neurological diseases, such as chronic pain, that involve dysregulated neurotransmission and neuroinflammation.

Cannabinoid type-1 receptor signaling in dopaminergic Engrailed-1 expressing neurons modulates motivation and depressive-like behavior.

The endocannabinoid system comprises highly versatile signaling functions within the nervous system. It is reported to modulate the release of several neurotransmitters, consequently affecting the activity of neuronal circuits. Investigations have highlighted its roles in numerous processes, including appetite-stimulating characteristics, particularly for palatable food. Moreover, endocannabinoids are shown to fine-tune dopamine-signaled processes governing motivated behavior. Specifically, it has been demonstrated that excitatory and inhibitory inputs controlled by the cannabinoid type 1 receptor (CB1) regulate dopaminergic neurons in the mesocorticolimbic pathway. In the present study, we show that mesencephalic dopaminergic (mesDA) neurons in the ventral tegmental area (VTA) express CB1, and we investigated the consequences of specific deletion of CB1 in cells expressing the transcription factor Engrailed-1 (En1). To this end, we validated a new genetic mouse line EN1-CB1-KO, which displays a CB1 knockout in mesDA neurons beginning from their differentiation, as a tool to elucidate the functional contribution of CB1 in mesDA neurons. We revealed that EN1-CB1-KO mice display a significantly increased immobility time and shortened latency to the first immobility in the forced swim test of adult mice. Moreover, the maximal effort exerted to obtain access to chocolate-flavored pellets was significantly reduced under a progressive ratio schedule. In contrast, these mice do not differ in motor skills, anhedonia- or anxiety-like behavior compared to wild-type littermates. Taken together, these findings suggest a depressive-like or despair behavior in an inevitable situation and a lack of motivation to seek palatable food in EN1-CB1-KO mice, leading us to propose that CB1 plays an important role in the physiological functions of mesDA neurons. In particular, our data suggest that CB1 directly modifies the mesocorticolimbic pathway implicated in depressive-like/despair behavior and motivation. In contrast, the nigrostriatal pathway controlling voluntary movement seems to be unaffected.

Sex-Specific Differences and the Role of Environmental Enrichment in the Expression of Hippocampal CB1 Receptors following Chronic Unpredictable Stress.

Stress-related mental disorders have become increasingly prevalent, thus endangering mental health worldwide. Exploring stress-associated brain alterations is vital for understanding the possible neurobiological mechanisms underlying these changes. Based on existing evidence, the brain endogenous cannabinoid system (ECS) plays a significant role in the stress response, and disruptions in its function are associated with the neurobiology of various stress-related disorders. This study primarily focuses on investigating the impact of chronic unpredictable stress (CUS) on the expression of hippocampal cannabinoid type 1 (CB1) receptors, part of the ECS, in adult male and female Wistar rats. Additionally, it explores whether environmental enrichment (EE) initiated during adolescence could mitigate the CUS-associated alterations in CB1 expression. Wistar rats, shortly after weaning, were placed in either standard housing (SH) or EE conditions for a duration of 10 weeks. On postnatal day 66, specific subgroups of SH or EE animals underwent a 4-week CUS protocol. Western blot (WB) analysis was conducted in the whole hippocampus of the left brain hemisphere to assess total CB1 protein expression, while immunohistochemistry (IHC) was performed on the right hemisphere to estimate the expression of CB1 receptors in certain hippocampal areas (i.e., CA1, CA3 and dentate gyrus-DG). The WB analysis revealed no statistically significant differences in total CB1 protein levels among the groups; however, reduced CB1 expression was found in specific hippocampal sub-regions using IHC. Specifically, CUS significantly decreased CB1 receptor expression in the CA1 and DG of both sexes, whereas in CA3 the CUS-associated decrease was limited to SH males. Interestingly, EE housing proved protective against these reductions. These findings suggest a region and sex-specific endocannabinoid response to chronic stress, emphasizing the role of positive early experiences in the protection of the adolescent brain against adverse conditions later in life.

Indirect and direct cannabinoid agonists differentially affect mesolimbic dopamine release and related behaviors.

The cannabinoid system is being researched as a potential pharmaceutical target for a multitude of disorders. The present study examined the effect of indirect and direct cannabinoid agonists on mesolimbic dopamine release and related behaviors in C57BL/6J (B6) mice. The indirect cannabinoid agonist N-arachidonoyl serotonin (AA-5-HT) indirectly agonizes the cannabinoid system by preventing the metabolism of endocannabinoids through fatty acid amide hydrolase inhibition while also inhibiting transient receptor potential vanilloid Type 1 channels. Effects of AA-5-HT were compared with the direct cannabinoid receptor Type 1 agonist arachidonoyl-2'-chloroethylamide (ACEA). In Experiment 1, mice were pretreated with seven daily injections of AA-5-HT, ACEA, or vehicle prior to assessments of locomotor activity using open field (OF) testing and phasic dopamine release using in vivo fixed potential amperometry. Chronic exposure to AA-5-HT did not alter locomotor activity or mesolimbic dopamine functioning. Chronic exposure to ACEA decreased rearing and decreased phasic dopamine release while increasing the dopaminergic response to cocaine. In Experiment 2, mice underwent AA-5-HT, ACEA, or vehicle conditioned place preference, then saccharin preference testing, a measure commonly associated with anhedonia. Mice did not develop a conditioned place preference or aversion for AA-5-HT or ACEA, and repeated exposure to AA-5-HT or ACEA did not alter saccharin preference. Altogether, the findings suggest that neither of these drugs induce behaviors that are classically associated with abuse liability in mice; however, direct cannabinoid receptor Type 1 agonism may play more of a role in mediating mesolimbic dopamine functioning than indirect cannabinoid agonism. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Cannabinoid type 2 receptor inhibition enhances the antidepressant and proneurogenic effects of physical exercise after chronic stress

Chronic stress is a major risk factor for neuropsychiatric conditions such as depression. Adult hippocampal neurogenesis (AHN) has emerged as a promising target to counteract stress-related disorders given the ability of newborn neurons to facilitate endogenous plasticity. Recent data sheds light on the interaction between cannabinoids and neurotrophic factors underlying the regulation of AHN, with important effects on cognitive plasticity and emotional flexibility. Since physical exercise (PE) is known to enhance neurotrophic factor levels, we hypothesised that PE could engage with cannabinoids to influence AHN and that this would result in beneficial effects under stressful conditions. We therefore investigated the actions of modulating cannabinoid type 2 receptors (CB2R), which are devoid of psychotropic effects, in combination with PE in chronically stressed animals. We found that CB2R inhibition, but not CB2R activation, in combination with PE significantly ameliorated stress-evoked emotional changes and cognitive deficits. Importantly, this combined strategy critically shaped stress-induced changes in AHN dynamics, leading to a significant increase in the rates of cell proliferation and differentiation of newborn neurons, overall reduction in neuroinflammation, and increased hippocampal levels of BDNF. Together, these results show that CB2Rs are crucial regulators of the beneficial effects of PE in countering the effects of chronic stress. Our work emphasises the importance of understanding the mechanisms behind the actions of cannabinoids and PE and provides a framework for future therapeutic strategies to treat stress-related disorders that capitalise on lifestyle interventions complemented with endocannabinoid pharmacomodulation.

Adenosine receptors are the on-and-off switch of astrocytic cannabinoid type 1 (CB1) receptor effect upon synaptic plasticity in the medial prefrontal cortex.

The medial prefrontal cortex (mPFC) is involved in cognitive functions such as working memory. Astrocytic cannabinoid type 1 receptor (CB1R) induces cytosolic calcium (Ca2+) concentration changes with an impact on neuronal function. mPFC astrocytes also express adenosine A1 and A2A receptors (A1R, A2AR), being unknown the crosstalk between CB1R and adenosine receptors in these cells. We show here that a further level of regulation of astrocyte Ca2+ signaling occurs through CB1R-A2AR or CB1R-A1R heteromers that ultimately impact mPFC synaptic plasticity. CB1R-mediated Ca2+ transients increased and decreased when A1R and A2AR were activated, respectively, unveiling adenosine receptors as modulators of astrocytic CB1R. CB1R activation leads to an enhancement of long-term potentiation (LTP) in the mPFC, under the control of A1R but not of A2AR. Notably, in IP3R2KO mice, that do not show astrocytic Ca2+ level elevations, CB1R activation decreases LTP, which is not modified by A1R or A2AR. The present work suggests that CB1R has a homeostatic role on mPFC LTP, under the control of A1R, probably due to physical crosstalk between these receptors in astrocytes that ultimately alters CB1R Ca2+ signaling.