Local activation of CB1 receptors by synthetic and endogenous cannabinoids dampens burst firing mode of reticular thalamic nucleus neurons in rats under ketamine anesthesia.

The reticular thalamic nucleus (RTN) is a thin shell that covers the dorsal thalamus and controls the overall information flow from the thalamus to the cerebral cortex through GABAergic projections that contact thalamo-cortical neurons (TC). RTN neurons receive glutamatergic afferents fibers from neurons of the sixth layer of the cerebral cortex and from TC collaterals. The firing mode of RTN neurons facilitates the generation of sleep-wake cycles; a tonic mode or desynchronized mode occurs during wake and REM sleep and a burst-firing mode or synchronized mode is associated with deep sleep. Despite the presence of cannabinoid receptors CB1 (CB1Rs) and mRNA that encodes these receptors in RTN neurons, there are few works that have analyzed the participation of endocannabinoid-mediated transmission on the electrical activity of RTN. Here, we locally blocked or activated CB1Rs in ketamine anesthetized rats to analyze the spontaneous extracellular spiking activity of RTN neurons. Our results show the presence of a tonic endocannabinoid input, since local infusion of AM 251, an antagonist/inverse agonist, modifies RTN neurons electrical activity; furthermore, local activation of CB1Rs by anandamide or WIN 55212-2 produces heterogeneous effects in the basal spontaneous spiking activity, where the main effect is an increase in the spiking rate accompanied by a decrease in bursting activity in a dose-dependent manner; this effect is inhibited by AM 251. In addition, previous activation of GABA-A receptors suppresses the effects of CB1Rs on reticular neurons. Our results show that local activation of CB1Rs primarily diminishes the burst firing mode of RTn neurons.

Inhibition of fatty acid amide hydrolase reverses aberrant prefrontal gamma oscillations in the sub-chronic PCP model for schizophrenia.

Hypofunctioning of NMDA receptors, and the resulting shift in the balance between excitation and inhibition, is considered a key process in the pathophysiology of schizophrenia. One important manifestation of this phenomenon is changes in neural oscillations, those above 30 Hz (i.e., gamma-band oscillations), in particular. Although both preclinical and clinical studies observed increased gamma activity following acute administration of NMDA receptor antagonists, the relevance of this phenomenon has been recently questioned given the reduced gamma oscillations typically observed during sensory and cognitive tasks in schizophrenia. However, there is emerging, yet contradictory, evidence for increased spontaneous gamma-band activity (i.e., at rest or under baseline conditions). Here, we use the sub-chronic phencyclidine (PCP) rat model for schizophrenia, which has been argued to model the pathophysiology of schizophrenia more closely than acute NMDA antagonism, to investigate gamma oscillations (30-100 Hz) in the medial prefrontal cortex of anesthetized animals. While baseline gamma oscillations were not affected, oscillations induced by train stimulation of the posterior dorsal CA1 (pdCA1) field of the hippocampus were enhanced in PCP-treated animals (5 mg/kg, twice daily for 7 days, followed by a 7-day washout period). This effect was reversed by pharmacological enhancement of endocannabinoid levels via systemic administration of URB597 (0.3 mg/kg), an inhibitor of the catabolic enzyme of the endocannabinoid anandamide. Intriguingly, the pharmacological blockade of CB1 receptors by AM251 unmasked a reduced gamma oscillatory activity in PCP-treated animals. The findings are consistent with the observed effects of URB597 and AM251 on behavioral deficits reminiscent of the symptoms of schizophrenia and further validate the potential for cannabinoid-based drugs as a treatment for schizophrenia.

Neuroprotection and Beyond: The Central Role of CB1 and CB2 Receptors in Stroke Recovery.

The endocannabinoid system, with its intricate presence in numerous cells, tissues, and organs, offers a compelling avenue for therapeutic interventions. Central to this system are the cannabinoid receptors 1 and 2 (CB1R and CB2R), whose ubiquity can introduce complexities in targeted treatments due to their wide-ranging physiological influence. Injuries to the central nervous system (CNS), including strokes and traumatic brain injuries, induce localized pro-inflammatory immune responses, termed neuroinflammation. Research has shown that compensatory immunodepression usually follows, and these mechanisms might influence immunity, potentially affecting infection risks in patients. As traditional preventive treatments like antibiotics face challenges, the exploration of immunomodulatory therapies offers a promising alternative. This review delves into the potential neuroprotective roles of the cannabinoid receptors: CB1R's involvement in mitigating excitotoxicity and CB2R's dual role in promoting cell survival and anti-inflammatory responses. However, the potential of cannabinoids to reduce neuroinflammation must be weighed against the risk of exacerbating immunodepression. Though the endocannabinoid system promises numerous therapeutic benefits, understanding its multifaceted signaling mechanisms and outcomes remains a challenge.

Memory impairment was ameliorated by corticolimbic microinjections of arachidonylcyclopropylamide (ACPA) and miRNA-regulated lentiviral particles in a streptozotocin-induced Alzheimer's rat model.

The present study aimed to investigate the effect of corticolimbic cannabinoid CB1 receptors activity on memory impairment in the intracerebroventricular (ICV)-streptozotocin (STZ) animal model of Alzheimer's like-disease. This study also assessed whether the corticolimbic overexpression of miRNA-137 or -let-7a could increase the endocannabinoids by inhibiting the monoglyceride lipase (MAGL) to ameliorate STZ response. The results showed that ICV microinjection of STZ (3 mg/kg/10 µl) impaired passive avoidance memory retrieval. The chronic microinjection of arachidonylcyclopropylamide (ACPA; 10 ng/0.5 µl), a selective cannabinoid CB1 receptor agonist, into the hippocampal CA1 region, the central amygdala (CeA) or the medial prefrontal cortex (mPFC) ameliorated the amnesic effect of ICV-STZ. Intra-CA1 or -CeA microinjection of ACPA alone did not affect memory retrieval, while its microinjection into the mPFC impaired memory formation. Based on bioinformatics analysis and verification of the MAGL gene, miRNA-137 and -let-7a were chosen to target the expression levels of MAGL in the corticolimbic regions. The chronic corticolimbic microinjection of lentiviral particles containing miRNA-137 or -let-7a ameliorated ICV-STZ-induced memory impairment. The high transfection efficiency was determined for each virus using comparing fluorescent and conventional vision. Corticolimbic overexpression of miRNA-137 or -let-7a decreased the MAGL gene expression that encodes the MAGL enzyme to increase the endocannabinoids. Thus, among the molecular mechanisms and signaling pathways involved in the pathophysiology of Alzheimer's disease (AD), it is worth mentioning the role of endocannabinoids in the corticolimbic regions. CB1 receptor agonists, miRNA-137 or -let-7a, may be potential therapeutic targets against cognitive decline in AD.

Therapeutic potential of a novel peripherally restricted CB1R inverse agonist on the progression of diabetic nephropathy.

Objective: This study assessed the efficacy of INV-202, a novel peripherally restricted cannabinoid type-1 receptor (CB1R) inverse agonist, in a streptozotocin-induced type-1 diabetes nephropathy mouse model. Methods: Diabetes was induced in 8-week-old C57BL6/J male mice via intraperitoneal injection of streptozotocin (45 mg/kg/day for 5 days); nondiabetic controls received citrate buffer. Diabetic mice were randomized to 3 groups based on blood glucose, polyuria, and albuminuria, and administered daily oral doses for 28-days of INV-202 at 0.3 or 3 mg/kg or vehicle. Results: INV-202 did not affect body weight but decreased kidney weight compared with the vehicle group. While polyuria was unaffected by INV-202 treatment, urinary urea (control 30.77 ± 14.93; vehicle 189.81 ± 31.49; INV-202 (0.3 mg/kg) 127.76 ± 20; INV-202 (3 mg/kg) 93.70 ± 24.97 mg/24h) and albumin (control 3.06 ± 0.38; vehicle 850.08 ± 170.50; INV-202 (0.3 mg/kg) 290.65 ± 88.70; INV-202 (3 mg/kg) 111.29 ± 33.47 µg/24h) excretion both decreased compared with vehicle-treated diabetic mice. Compared with the vehicle group, there was a significant improvement in the urinary albumin to creatinine ratio across INV-202 groups. Regardless of the dose, INV-202 significantly reduced angiotensin II excretion in diabetic mice. The treatment also decreased Agtr1a renal expression in a dose-dependent manner. Compared with nondiabetic controls, the glomerular filtration rate was increased in the vehicle group and significantly decreased by INV-202 at 3 mg/kg. While the vehicle group showed a significant loss in the mean number of podocytes per glomerulus, INV-202 treatment limited podocyte loss in a dose-dependent manner. Moreover, in both INV-202 groups, expression of genes coding for podocyte structural proteins nephrin (Nphs1), podocin (Nphs2), and podocalyxin (Pdxl) were restored to levels similar to nondiabetic controls. INV-202 partially limited the proximal tubular epithelial cell (PTEC) hyperplasia and normalized genetic markers for PTEC lesions. INV-202 also reduced expression of genes contributing to oxidative stress (Nox2, Nox4, and P47phox) and inflammation (Tnf). In addition, diabetes-induced renal fibrosis was significantly reduced by INV-202. Conclusions: INV-202 reduced glomerular injury, preserved podocyte structure and function, reduced injury to PTECs, and ultimately reduced renal fibrosis in a streptozotocin-induced diabetic nephropathy mouse model. These results suggest that INV-202 may represent a new therapeutic option in the treatment of diabetic kidney disease.

Type-1 cannabinoid receptors and their ever-expanding roles in brain energy processes.

The brain requires large quantities of energy to sustain its functions. At the same time, the brain is isolated from the rest of the body, forcing this organ to develop strategies to control and fulfill its own energy needs. Likely based on these constraints, several brain-specific mechanisms emerged during evolution. For example, metabolically specialized cells are present in the brain, where intercellular metabolic cycles are organized to separate workload and optimize the use of energy. To orchestrate these strategies across time and space, several signaling pathways control the metabolism of brain cells. One of such controlling systems is the endocannabinoid system, whose main signaling hub in the brain is the type-1 cannabinoid (CB1 ) receptor. CB1 receptors govern a plethora of different processes in the brain, including cognitive function, emotional responses, or feeding behaviors. Classically, the mechanisms of action of CB1 receptors on brain function had been explained by its direct targeting of neuronal synaptic function. However, new discoveries have challenged this view. In this review, we will present and discuss recent data about how a small fraction of CB1 receptors associated to mitochondrial membranes (mtCB1 ), are able to exert a powerful control on brain functions and behavior. mtCB1 receptors impair mitochondrial functions both in neurons and astrocytes. In the latter cells, this effect is linked to an impairment of astrocyte glycolytic function, resulting in specific behavioral outputs. Finally, we will discuss the potential implications of (mt)CB1 expression on oligodendrocytes and microglia metabolic functions, with the aim to encourage interdisciplinary approaches to better understand the role of (mt)CB1 receptors in brain function and behavior.

Cannabidiol-Decorated Berberine-Loaded Microemulsions Improve IBS-D Therapy Through Ketogenic Diet-Induced Cannabidiol Receptors Overexpression.

Background: Berberine (BR) shows promise as a candidate for treating irritable bowel syndrome with diarrhea (IBS-D). However, the undesired physicochemical properties and poor oral absorption limit its clinical translation. A ketogenic diet (KD) can induce intestinal overexpression of cannabidiol (CB) receptors, which may offer a potential target for IBS-D-specific delivery of BR. Methods: The microemulsions loaded with BR and decorated with cannabidiol (CBD/BR-MEs) were developed through a one-step emulsion method. The pharmaceutical behaviors of the CBD/BR-MEs were measured using dynamic light scattering and high-performance liquid chromatography. The efficacy of the anti-IBS-D therapy was evaluated by assessing fecal water content, Bristol score, and AWR score. The intestinal permeability were assessed through immunofluorescent staining of CB1 and ZO-1, respectively. The signaling of CREB/BDNF/c-Fos was also studied along with immunofluorescent and immunohistochemical examination of brain sections. Results: The CBD/BR-MEs, which had a particle size of approximately 30 nm and a surface density of 2% (wt%) CBD, achieved greater than 80% (wt%) encapsulation efficiency of BR. The pharmacokinetics performance of CBD/BR-MEs was significantly improved in the KD-fed IBS-D rats than the standard diet-fed ones, which is highly related to intestinal expression of CB1 receptors. The treatment with CBD/BR-MEs and KD exhibited evident comprehensive advantages over the other groups in terms of anti-IBS-D efficacy. CBD/BR-MEs and KD synergistically decreased intestinal permeability. Moreover, the treatment with CBD/BR-MEs and KD not only blocked the CREB/BDNF/c-Fos signaling in the brain but also decreased the levels of neurotrophic factors, neurotransmitters, and inflammatory cytokines in the serum of IBS-D model rats. Conclusion: Such a design represents the first attempt at IBS-D-targeted drug delivery for improved oral absorption and efficacy through KD-induced target exposure, which holds promising potential for the treatment of IBS-D.

Cannabidiol interacts with the FXR/Nrf2 pathway and changes the CB1/CB2 receptors ratio in gentamicin-induced kidney injury in rats.

Objectives: Gentamicin-induced nephrotoxicity was used as an experimental model of kidney disease. The present study was performed to assess the therapeutic role of cannabidiol (CBD) against gentamicin-induced renal damage. Materials and Methods: Forty two male Wistar rats were randomly allocated into 6 groups (n=7), including: (1) Control, (2) Vehicle, (3) Gentamicin-treated group (100 mg/kg/day) for 10 days (GM), (4-6) 3 Gentamicin-CBD-treated groups (2.5, 5, and 10 mg/kg/day) for 10 days (GM+CBD2.5, GM+CBD5, GM+CBD10). Serum levels of BUN and Cr, renal histology as well as real-time qRT-PCR were used to investigate the pattern of changes at different levels. Results: Gentamicin increased serum BUN and Cr (P<0.001), down-regulation of FXR (P<0.001), SOD (P<0.05) and up-regulation of CB1 receptor mRNA (P<0.01). Compared to the control group, CBD at 5 decreased (P<0.05) and at 10 mg/kg/day increased the expression of FXR (P<0.05). Nrf2 expression in CBD groups was increased (P<0.001 vs. GM). The expression of TNF-α compared to the control and GM groups, was significantly increased in CBD2.5 (P<0.01) and CBD10 (P<0.05). Compared to the control, CBD at 2.5 (P<0.01), 5 (P<0.001) and 10 (P<0.001) mg/kg/day significantly increased the expression of CB1R. Up-regulation of CB1R in the GM+CBD5, was significantly higher (P<0.05) than the GM group. Compared to the control group, the most significant increase in CB2 receptor expression was observed at CBD10 (P<0.05). Conclusion: CBD particularly at 10 mg/kg/day might be of significant therapeutic benefit against such renal complications. Activating the FXR/Nrf2 pathway and counteracting the deleterious effects of CB1 receptors via CB2 receptors scale-up could be part of the protective mechanisms of CBD.

Astroglial CB1 receptors, energy metabolism, and gliotransmission: an integrated signaling system?

Astrocytes are key players in brain homeostasis and function. During the last years, several studies have cemented this notion by showing that these cells respond to neuronal signals and, via the release of molecules that modulate and support synaptic activity (gliotransmission) participates in the functions of the so-called tripartite synapse. Thus, besides their established control of brain metabolism, astrocytes can also actively control synaptic activity and behavior. Among the signaling pathways that shape the functions of astrocyte, the cannabinoid type-1 (CB1) receptor is emerging as a critical player in the control of both gliotransmission and the metabolic cooperation between astrocytes and neurons. In the present short review, we describe known and newly discovered properties of the astroglial CB1 receptors and their role in modulating brain function and behavior. Based on this evidence, we finally discuss how the functions and mode of actions of astrocyte CB1 receptors might represent a clear example of the inextricable relationship between energy metabolism and gliotransmission. These tight interactions will need to be taken into account for future research in astrocyte functions and call for a reinforcement of the theoretical and experimental bridges between studies on metabolic and synaptic functions of astrocytes.

Underlying mechanisms of long-term potentiation during the inhibition of the cannabinoid CB1 and GABAB receptors in the dentate gyrus of hippocampus.

BACKGROUND: The release of various neurotransmitters and thereby the excitability of neuronal circuits are regulated by the endocannabinoid system in an activity-dependent manner. Hippocampal long-term potentiation (LTP) is augmented in cannabinoid type 1 (CB1) receptor-deficient mice. CB1 receptors exist on GABAergic axon terminals in the hippocampus. In our previous work, we showed that CB1 antagonists increased the population spike (PS) amplitude, field excitatory post-synaptic potential (fEPSP), and the LTP induction in the dentate gyrus (DG) of the rat hippocampus while the GABAB antagonist decreased these parameters. Determining the underlying mechanisms of the pre- and/or postsynaptic locus of LTP expression is of great importance. In this study, we investigated whether LTP alteration acutely caused by CB1 and GABAB receptor antagonists (AM251 and CGP55845, respectively) happens at the postsynaptic or presynaptic regions, or at both. Therefore, the paired-pulse ratio (PPR) was assessed prior to and following the LTP induction in the studied groups. METHODS: Male Wistar rats were randomly assigned to the groups of control, AM251, CGP55845, CGP55845 + AM251. A high-frequency stimulation (HFS) of the perforant path (PP) was used to induce LTP in the DG region. RESULTS: Statistical analysis revealed that AM251 produced significant increase in excitatory postsynaptic potential (EPSP) slope and amplitude of PS. Conversely, administration of CGP55845 produced decrease in slope of EPSP. The current results indicated that the PPR was not influenced by LTP induction in the presence of AM251 or CGP55845 either alone or their combination. CONCLUSIONS: It can be concluded that the site causing LTP expression is, at least in part, the postsynaptic site because PPR was not influenced by LTP induction in the presence of AM251 or CGP55845 either alone or their combination.

Differential regulation of Cav 3.2 and Cav 2.2 calcium channels by CB1 receptors and cannabidiol.

BACKGROUND AND PURPOSE: Cannabinoids are a promising therapeutic avenue for chronic pain. However, clinical trials often fail to report analgesic efficacy of cannabinoids. Inhibition of voltage gate calcium (Cav ) channels is one mechanism through which cannabinoids may produce analgesia. We hypothesized that cannabinoids and cannabinoid receptor agonists target different types of Cav channels through distinct mechanisms. EXPERIMENTAL APPROACH: Electrophysiological recordings from tsA-201 cells expressing either Cav 3.2 or Cav 2.2 were used to assess inhibition by HU-210 or cannabidiol (CBD) in the absence and presence of the CB1 receptor. Homology modelling assessed potential interaction sites for CBD in both Cav 2.2 and Cav 3.2. Analgesic effects of CBD were assessed in mouse models of inflammatory and neuropathic pain. KEY RESULTS: HU-210 (1 µM) inhibited Cav 2.2 function in the presence of CB1 receptor but had no effect on Cav 3.2 regardless of co-expression of CB1 receptor. By contrast, CBD (3 µM) produced no inhibition of Cav 2.2 and instead inhibited Cav 3.2 independently of CB1 receptors. Homology modelling supported these findings, indicating that CBD binds to and occludes the pore of Cav 3.2, but not Cav 2.2. Intrathecal CBD alleviated thermal and mechanical hypersensitivity in both male and female mice, and this effect was absent in Cav 3.2 null mice. CONCLUSION AND IMPLICATIONS: Our findings reveal differential modulation of Cav 2.2 and Cav 3.2 channels by CB1 receptors and CBD. This advances our understanding of how different cannabinoids produce analgesia through action at different voltage-gated calcium channels and could influence the development of novel cannabinoid-based therapeutics for treatment of chronic pain.

Age-dependent effects of estradiol on temporal memory: A role for the type 1 cannabinoid receptor?

This study investigated in male mice how age modulates the effects of acute 17ß-estradiol (E2) on dorsal CA1 (dCA1)-dependent retention of temporal associations, which are critical for declarative memory. E2 was systemically injected to young (3-4 months old) and aged (22-24 months old) adult mice either (i) 1 h before the acquisition of an auditory trace fear conditioning (TFC) procedure allowing the assessment of temporal memory retention 24 h later or (ii) during in vivo electrophysiological recordings of CA3 to dCA1 synaptic efficacy under anesthesia. In young mice, E2 induced parallel dose-dependent reductions in memory and synaptic efficacy, i.e. an impairment in TFC retention and a long-term (NMDA receptor-dependent) depression of dCA1 synaptic efficacy as assessed by field excitatory postsynaptic potentials. In contrast, E2 tended to improved TFC retention whilst failing to change synaptic efficacy in aged mice. Age-dependent effects of E2 treatment were confirmed by immunohistochemical analyses of TFC acquisition-elicited dCA1 Fos activation. Thus, such an activation was respectively reduced and enhanced in young and aged E2-treated mice, compared to vehicle treatments. Hippocampal mRNA expression of estrogen receptors by RT-PCR analyses revealed an age-related increase in each receptor mRNA expression. In keeping with the key role of the endocannabinoid system in memory processes and CA3 to dCA1 synaptic plasticity, we next examined the role of cannabinoid type 1 receptors (CB1-R) in the aforementioned age-dependent effects of E2. Having confirmed that mRNA expression of CB1-R diminishes with age, we then observed that the deleterious effects of E2 on both memory and synaptic efficacy were both prevented by the CB1-R antagonist Rimonabant whilst being absent in CB1-R knock out mice. This study (i) reveals age-dependent effects of acute E2 on temporal memory and CA3 to dCA1 synaptic efficacy and (ii) suggests a key role of CB1-R in mediating E2 deleterious effects in young adulthood. Aging-related reductions in CB1-R might thus underlie E2 paradoxical effects across age.

Targeting mediodorsal thalamic CB1 receptors to inhibit dextromethorphan-induced anxiety/exploratory-related behaviors in rats: The post-weaning effect of exercise and enriched environment on adulthood anxiety.

Dextromethorphan (DXM) is an effective over-the-counter antitussive with an alarming increase as an abused drug for recreational purposes. Although reports of the association between DXM administration and anxiety, there are few investigations into the underlying DMX mechanisms of anxiogenic action. Thus, the present study aimed to investigate the role of the mediodorsal thalamus (MD) cannabinoid CB1 receptors (CB1Rs) in DXM-induced anxiety/exploratory-related behaviors in adult male Wistar rats. Animals were bilaterally cannulated in the MD regions. After one week, anxiety and exploratory behaviors were measured using an elevated plus-maze task (EPM) and a hole-board apparatus. Results showed that DXM (3-7 mg/kg, i. p.) dose-dependently increased anxiety-like behaviors. Intra-MD administration of ACPA (2.5-10 ng/rat), a selective CB1 receptor agonist, decreased anxiety-like effects of DXM. The blockade of MD CB1 receptors by AM-251 (40-120 ng/rat) did not affect the EPM task. However, it potentiated the anxiogenic response of an ineffective dose of DXM (3 mg/kg) in the animals. Moreover, the effect of post-weaning treadmill exercise (TEX) and enriched environment (EE) were examined in adulthood anxiety under the drug treatments. Juvenile rats were divided into TEX/EE and control groups. The TEX/EE-juvenile rats were placed on a treadmill and then exposed to EE for five weeks. Interestingly, compared to untreated animals, post-weaning TEX/EE inhibited the anxiety induced by DXM or AM-251/DXM. It can be concluded that the MD endocannabinoid system plays an essential role in the anxiogenic effect of dextromethorphan. Moreover, post-weaning exercise alongside an enriched environment may have an inhibitory effect on adulthood anxiety-like behaviors.

Putative Activation of Cannabinoid Receptor Type 1 Prevents Brain Oxidative Stress and Inhibits Aggressive-Like Behavior in Zebrafish.

Background: Aggression is a set of complex behaviors commonly described in different neurological disorders, such as schizophrenia, autistim spectrum disorder, and anxiety. Previous studies have described that some changes in the redox status of the brain are closely associated with aggressive behavior in different species. In addition, the endocannabinoid system acts as a neuromodulator of the central nervous system, however, its participation in aggressive behavior needs to be elucidated. Danio rerio (zebrafish) is an important model in the study of aggression, in this context, the present study investigated whether the activation of type 1 cannabinoid receptors (CB1r) alters the cerebral redox state and aggressive behavior in zebrafish. Materials and Methods: We performed pharmacological manipulations with the CB1r agonist (ACEA) and antagonist (AM-251) to assess the role of this receptor in aggressive behavior. Individuals were isolated in pairs, without physical contact for 24 h, treated with the drugs of interest, and after 30 minutes of pharmacokinetics, the fights were filmed for 30 min, and the individuals were identified as dominant or subordinate. Results: A consistent decrease in the strike and bite aggressive behavior was observed in the group treated with the ACEA agonist compared with that in the control and AM-251 groups. When evaluating the cerebral redox state, we observed that treatment with the ACEA agonist reduced malondialdehyde (MDA) levels and increased the levels of sulfhydryl groups compared with those in the control group. These results indicate that the activation of CB1r by the ACEA agonist inhibited aggressiveness and attenuated the levels of oxidative stress in both subjects (dominant or subordinate) in the treated group. Conclusion: Thus, we suggest that zebrafish is an alternative model to study common aggressive behavior disorders among species and that CB1r represent a potential target for the development of treatments for aggressive disorders.

Electroacupuncture reduces chronic itch via cannabinoid CB1 receptors in the ventrolateral periaqueductal gray.

Chronic itch severely reduces the quality of life of patients. Electroacupuncture (EA) is widely used to treat chronic itch. However, the underlying mechanism of this therapeutic action of EA is largely unknown. Cannabinoid CB1 receptors in the ventrolateral periaqueductal gray (vlPAG) mediate the analgesic effect of EA. Using a dry skin-induced itch model in mice, we determined whether EA treatment reduces chronic itch via CB1 receptors in the vlPAG. We showed that the optimal inhibitory effect of EA on chronic itch was achieved at the high frequency and high intensity (100 Hz and 3 mA) at "Quchi" (LI11) and "Hegu" (LI14) acupoints, which are located in the same spinal dermatome as the cervical skin lesions. EA reversed the increased expression of CB1 receptors in the vlPAG and decreased the concentration of 5-hydroxytryptamine (5-HT) in the medulla oblongata and the expression of gastrin-releasing peptide receptors (GRPR) in the cervical spinal cord. Furthermore, knockout of CB1 receptors on GABAergic neurons in the vlPAG attenuated scratching behavior and the 5-HT concentration in the medulla oblongata. In contrast, knockout of CB1 receptors on glutamatergic neurons in the vlPAG blocked the antipruritic effects of EA and the inhibitory effect of EA on the 5-HT concentration in the medulla oblongata. Our findings suggest that EA treatment reduces chronic itch by activation of CB1 receptors on glutamatergic neurons and inhibition of CB1 receptors on GABAergic neurons in the vlPAG, thereby inhibiting the 5-HT release from the medulla oblongata to GRPR-expressing neurons in the spinal cord. Our findings suggest that EA attenuates chronic itch via activating CB1 receptors expressed on glutamatergic neurons and downregulating CB1 receptors on GABAergic neurons in the vlPAG, leading to the reduction in 5-HT release in the rostroventral medulla and GRPR signaling in the spinal cord. Our study not only advances our understanding of the mechanisms of the therapeutic effect of EA on chronic itch but also guides the selection of optimal parameters and acupoints of EA for treating chronic itch.

Roles of cannabinoid CB1 and CB2 receptors in the modulation of psychostimulant responses.

Addiction to psychostimulant drugs, such as cocaine, D-amphetamine, and methamphetamine, is a public health issue that substantially contributes to the global burden of disease. Psychostimulant drugs promote an increase in dopamine levels within the mesocorticolimbic system, which is central to the rewarding properties of such drugs. Cannabinoid receptors (CB1R and CB2R) are expressed in the main areas of this system and implicated in the neuronal mechanisms underlying the rewarding effect of psychostimulant drugs. Here, we reviewed studies focusing on pharmacological intervention targeting cannabinoid CB1R and CB2R and their interaction in the modulation of psychostimulant responses.

Electroacupuncture Reduces Anxiety Associated With Inflammatory Bowel Disease By Acting on Cannabinoid CB1 Receptors in the Ventral Hippocampus in Mice.

The therapeutic effects of electroacupuncture (EA) on the comorbidity of visceral pain and anxiety in patients with inflammatory bowel disease (IBD) is well known. It has been known that the ventral hippocampus (vHPC) and the cannabinoid type 1 receptors (CB1R) are involved in regulating anxiety and pain. Therefore, in this study, we determined whether EA reduces visceral pain and IBD-induced anxiety via CB1R in the vHPC. We found that EA alleviated visceral hyperalgesia and anxiety in TNBS-treated IBD mice. EA reversed over-expression of CB1R in IBD mice and decreased the percentage of CB1R-expressed GABAergic neurons in the vHPC. Ablating CB1R of GABAergic neurons in the vHPC alleviated anxiety in TNBS-treated mice and mimicked the anxiolytic effect of EA. While ablating CB1R in glutamatergic neurons in the vHPC induced severe anxiety in wild type mice and inhibited the anxiolytic effect of EA. However, ablating CB1R in either GABAergic or glutamatergic neurons in the vHPC did not alter visceral pain. In conclusion, we found CB1R in both GABAergic neurons and glutamatergic neurons are involved in the inhibitory effect of EA on anxiety but not visceral pain in IBD mice. EA may exert anxiolytic effect via downregulating CB1R in GABAergic neurons and activating CB1R in glutamatergic neurons in the vHPC, thus reducing the release of glutamate and inhibiting the anxiety circuit related to vHPC. Thus, our study provides new information about the cellular and molecular mechanisms of the therapeutic effect of EA on anxiety induced by IBD.

Basolateral amygdala cannabinoid CB1 receptors mediate the antinociceptive activity of harmaline in adolescent male mice.

Evidence suggests a clear role for the amygdala endocannabinoid system in pain processing. Harmaline has been also known as the main nociceptive agent extracted from the Peganum harmala plant. In this study, the role of basolateral amygdala (BLA) cannabinoid CB1 receptors in pain sensitivity of harmaline-treated mice were assessed using tail-flick and hot plate methods in adolescent male NMRI mice. Intraperitoneal administration of two higher doses of harmaline (6 and 8 mg/kg) increased tail-flick latency, suggesting an antinociceptive activity. The same result was observed for the higher dose of harmaline in the hot plate test. Intra-BLA microinjection of CB1 receptor agonist ACPA (1 and 1.5 ng/mouse) or (1.5 ng/mouse) enhanced the ineffective dose-response of harmaline on pain threshold in the tail-flick or hot plate tests, respectively. Microinjection of two higher doses of CB1 receptor antagonist AM251 (0.5 and 1 ng/mouse) attenuated the antinociceptive activity of harmaline (8 ng/mouse) in both tail-flick and hot plate tests. Meanwhile, ACPA and AM251 did not alter latency to withdraw from the noxious stimulus in both tests, by themselves. It should be noted that the analgesic dose of the drugs alone or in combination did not affect locomotor activity. The obtained results highlight that BLA CB1 receptors mediate the antinociceptive activity of harmaline.

Neuroplastic alterations in cannabinoid receptors type 1 (CB1) in animal models of epileptic seizures.

Currently, there is an urgent need to better comprehend neuroplastic alterations in cannabinoid receptors type 1 (CB1) and to understand the biological meaning of these alterations in epileptic disorders. The present study reviewed neuroplastic changes in CB1 distribution, expression, and functionality in animal models of epileptic seizures. Neuroplastic alterations in CB1 were consistently observed in chemical, genetic, electrical, and febrile seizure models. Most studies assessed changes in hippocampal and cortical CB1, while thalamic, hypothalamic, and brainstem nuclei were rarely investigated. Additionally, the relationship between CB1 alteration and the control of brain excitability through modulation of specific neuronal networks, such as striatonigral, nigrotectal and thalamocortical pathways, and inhibitory projections to hippocampal pyramidal neurons, were all presented and discussed in the present review. Neuroplastic alterations in CB1 detected in animal models of epilepsy may reflect two different scenarios: (1) endogenous adaptations aimed to control neuronal hyperexcitability in epilepsy or (2) pathological alterations that facilitate neuronal hyperexcitability. Additionally, a better comprehension of neuroplastic and functional alterations in CB1 can improve pharmacological therapies for epilepsies and their comorbidities.