Role Of Cannabinoid CB1 Receptors Research Articles

CB1 Receptor Signaling: Linking Neuroplasticity, Neuronal Types, and Mental Health Outcomes.

The endocannabinoid system (ECS) is crucial in the pathophysiology of mental disorders. Historically, cannabis has been utilized for centuries to mitigate symptoms of anxiety and depression; however, the precise role of cannabinoids in these conditions has only recently garnered extensive research attention. Despite the growing body of literature on the ECS and its association with mental health, several critical questions remain unresolved. This review primarily focuses on cannabinoid CB1 receptors (CB1R), providing an examination of their regulatory roles in states related to mental disorders. Evidence suggests that CB1R distribution occurs among various neuronal types, astrocytes, and subcellular membranes across multiple brain regions, potentially exhibiting both analogous and antagonistic effects. Additionally, various forms of stress have been shown to produce divergent impacts on CB1R signaling pathways. Furthermore, numerous CB1R agonists demonstrate biphasic, dose-dependent effects on anxiety and depression; specifically, low doses may exert anxiolytic effects, while higher doses can induce anxiogenic responses, a phenomenon observed in both rodent models and human studies. We also discuss the diverse underlying mechanisms that mediate these effects. We anticipate that this review will yield valuable insights into the role of CB1R in mental disorders and provide a framework for future research endeavors on CB1R and the ECS. This knowledge may ultimately inform therapeutic strategies aimed at alleviating symptoms associated with mental health conditions.

Role of cannabinoid CB1 receptors in the proconvulsant effect of Apelin-13 on penicillin-induced epileptiform activity

Role of cannabinoid CB1 receptors in the proconvulsant effect of Apelin-13 on penicillin-induced epileptiform activity

ПАРАМЕТРЫ ПОХОДКИ КРЫС С ПЕРИФЕРИЧЕСКОЙ НЕЙРОПАТИЕЙ ПРИ ТРАНСПЛАНТАЦИИ МЕЗЕНХИМАЛЬНЫХ СТВОЛОВЫХ КЛЕТОК И ФАРМАКОЛОГИЧЕСКОЙ СТИМУЛЯЦИИ КАННАБИНОИДНЫХ РЕЦЕПТОРОВ II ТИПА

Background. The study of the role of cannabinoid CB2 receptors in the effectiveness of adipose-derived (AD) mesenchymal stem cells (MSCs) in preventing motor activity disorders in the affected limb will deepen understanding of the mechanisms of MSCs effects when administered locally. Aim. To evaluate the effect of pharmacological stimulation of cannabinoid CB2 receptors during transplantation of AD MSCs on changes in gait parameters in rats in a model of peripheral neuropathy. Material and methods. In 40 male Wistar rats peripheral neuropathic pain was modeled by sciatic nerve transection. On the 7th day after NP modeling, AD MSCs transplantation was performed without additional interventions upon the pharmacological stimulation of CB2 receptors in the area of sciatic nerve transection, as well as after stimulation of CB2 receptors on the AD MSCs membranes during pretreatment. Within 90 days a detailed analysis of the gait was carried out using the CatWalk XT 10.6. Results. Transplantation of AD MSCs accelerated the recovery of dynamic gait parameters, as well as sciatic functional index, and abolished the development of static gait disturbances in rats after sciatic nerve transection. Significant differences in the analyzed gait parameters in the study groups with AD MSCs transplantation were not found. Conclusion. Pharmacological stimulation of CB2 receptors did not enhance or suppress the effect of AD MSCs on the rate of recovery of gait parameters in experimental animals.

The role of cannabinoid CB1 receptors in the antinociceptive and reparative actions of mesenchymal stem cells in rats with peripheral neuropathic pain.

Mesenchymal stem cells (MSCs) can produce antinociceptive and reparative effects. Presumably, the MSCs-induced antinociception may be partly due to the involvement of the endocannabinoid system. The study aimed to evaluate the antinociceptive and reparative effects of adipose-derived MSCs (ADMSCs) upon pharmacological modulation of cannabinoid CB1 receptor in peripheral tissues or on ADMSCs' membranes in a rat model of peripheral neuropathy. ADMSCs were injected into the area of rat sciatic nerve injury (i) with no additional treatments, (ii) at the tissue CB1 receptor activation by endogenous agonist anandamide (AEA) or blockade with a selective AM251 antagonist; and (iii) preincubated with AEA or AM251. The evaluation of CB1 receptor activity involved analyzing nociceptive responses, gait parameters, and histology. Transplantation of ADMSCs upon activation of CB1 receptors, both on AMSCs' membranes or in the area of nerve injury, accelerated the analgesia and recovery of dynamic gait parameters, abolished static gait disturbances, and promoted the fastest nerve regeneration. Only blockade of CB1 receptors on ADMSCs shortened ADMSCs-induced analgesia and decreased the number of preserved nerve fibers. CB1 receptors on ADMSCs significantly contribute to their pain-relieving and tissue-repairing capabilities by stimulating the growth factors secretion and suppressing the release of pro-inflammatory cytokines. Peripheral CB1 receptors do not significantly influence ADMSC-induced antinociception.

Role of Cannabinoid CB2 Receptor in Alcohol Use Disorders: From Animal to Human Studies

Cumulative evidence has pointed out cannabinoid CB2 receptors (CB2r) as a potential therapeutic key target for treating alcohol use disorder (AUD). This review provides the most relevant results obtained from rodent and human studies, including an integrative section focused on the involvement of CB2r in the neurobiology of alcohol addiction. A literature search was conducted using the electronic databases Medline and Scopus for articles. The search strategy was as follows: “Receptor, Cannabinoid, CB2” AND “Alcohol-Related Disorders” AND “human/or patients”; “Receptor, Cannabinoid, CB2” AND “Alcohol” OR “Ethanol” AND “rodents/or mice/or rats”. Pharmacological approaches demonstrated that the activation or blockade of CB2r modulated different alcohol-addictive behaviors. Rodent models of alcoholism revealed significant alterations of CB2r in brain areas of the reward system. In addition, mice lacking CB2r (CB2KO) show increased alcohol consumption, motivation, and relapse alterations. It has been stressed that the potential neurobiological mechanisms underlying their behavioral effects involve critical elements of the alcohol reward system. Interestingly, recent postmortem studies showed CNR2 alterations in brain areas of alcoholic patients. Moreover, although the number of studies is limited, the results revealed an association between some genetic alterations of the CNR2 and an increased risk for developing AUD. This review provides evidence that CB2r may play a role in alcohol addiction. Clinical studies are necessary to figure out whether CB2r ligands may prove useful for the treatment of AUD in humans.

A Novel Highly Selective Cannabinoid CB2 Agonist Reduces in vitro Growth and TGF-beta Release of Human Glial Cell Tumors

Cannabinoid receptors have been detected in human gliomas and cannabinoids have been proposed as novel drug candidates in the treatment of brain tumors. To test the in vitro antitumor activity of COR167, a novel cannabinoid CB2-selective agonist displaying a high binding affinity for human CB2 receptors, on tumor cells isolated from human glioblastoma multiforme and anaplastic astrocytoma. Glioma cell cultures were established from two glioblastoma multiforme and two anaplastic astrocytomas. Proliferation was measured in the presence or absence of COR167 with a bromodeoxyuridine (BrdU) cell proliferation ELISA assay. CB2 receptor expression was detected by western blotting. Apoptosis was assessed with phycoerythrin (PE) annexin V flow cytometry kit. TGF-beta 1 and 2 levels were analyzed in culture supernatants with commercial ELISAs. COR167 was found to significantly reduce the proliferation of both glioblastoma and anaplastic astrocytoma in a dose-dependent manner at lower doses than other known, less specific CB2 agonists. This activity is independent of apoptosis and is associated with a significant reduction of TGF-beta 1 and 2 levels in supernatants of glioma cell cultures. These findings add to the role of cannabinoid CB2 receptor as a possible pharmacological target to counteract glial tumor growth and encourage further work to explore any other pharmacological effect of this novel CB2 agonist useful in the treatment of human gliomas.

Genetic or pharmacological depletion of cannabinoid CB1 receptor protects against dopaminergic neurotoxicity induced by methamphetamine in mice

Accumulating evidence suggests that cannabinoid ligands play delicate roles in cell survival and apoptosis decisions, and that cannabinoid CB1 receptors (CB1R) modulate dopaminergic function. However, the role of CB1R in methamphetamine (MA)-induced dopaminergic neurotoxicity in vivo remains elusive. Multiple high doses of MA increased phospho-ERK and CB1R mRNA expressions in the striatum of CB1R (+/+) mice. These increases were attenuated by CB1R antagonists (i.e., AM251 and rimonabant), an ERK inhibitor (U0126), or dopamine D2R antagonist (sulpiride). In addition, treatment with MA resulted in dopaminergic impairments, which were attenuated by CB1R knockout or CB1R antagonists (i.e., AM251 and rimonabant). Consistently, MA-induced oxidative stresses (i.e., protein oxidation, lipid peroxidation and reactive oxygen species) and pro-apoptotic changes (i.e., increases in Bax, cleaved PKCδ- and cleaved caspase 3-expression and decrease in Bcl-2 expression) were observed in the striatum of CB1R (+/+) mice. These toxic effects were attenuated by CB1R knockout or CB1R antagonists. Consistently, treatment with four high doses of CB1R agonists (i.e., WIN 55,212-2 36mg/kg and ACEA 16mg/kg) also resulted in significant oxidative stresses, pro-apoptotic changes, and dopaminergic impairments. Since CB1R co-immunoprecipitates PKCδ in the presence of MA or CB1R agonists, we applied PKCδ knockout mice to clarify the role of PKCδ in the neurotoxicity elicited by CB1Rs. CB1R agonist-induced toxic effects were significantly attenuated by CB1R knockout, CB1R antagonists or PKCδ knockout. Therefore, our results suggest that interaction between D2R, ERK and CB1R is critical for MA-induced dopaminergic neurotoxicity and that PKCδ mediates dopaminergic damage induced by high-doses of CB1R agonist.

P.6.c.017 - Role of cannabinoid CB1 receptor in cocaine-induced sensitization and conditioned place preference

P.6.c.017 - Role of cannabinoid CB1 receptor in cocaine-induced sensitization and conditioned place preference

Stimulation of brain glucose uptake by cannabinoid CB2 receptors and its therapeutic potential in Alzheimer's disease

Cannabinoid CB2 receptors (CB2Rs) are emerging as important therapeutic targets in brain disorders that typically involve neurometabolic alterations. We here addressed the possible role of CB2Rs in the regulation of glucose uptake in the mouse brain. To that aim, we have undertaken 1) measurement of 3H-deoxyglucose uptake in cultured cortical astrocytes and neurons and in acute hippocampal slices; 2) real-time visualization of fluorescently labeled deoxyglucose uptake in superfused hippocampal slices; and 3) in vivo PET imaging of cerebral 18F-fluorodeoxyglucose uptake. We now show that both selective (JWH133 and GP1a) as well as non-selective (WIN55212-2) CB2R agonists, but not the CB1R-selective agonist, ACEA, stimulate glucose uptake, in a manner that is sensitive to the CB2R-selective antagonist, AM630. Glucose uptake is stimulated in astrocytes and neurons in culture, in acute hippocampal slices, in different brain areas of young adult male C57Bl/6j and CD-1 mice, as well as in middle-aged C57Bl/6j mice. Among the endocannabinoid metabolizing enzymes, the selective inhibition of COX-2, rather than that of FAAH, MAGL or α,βDH6/12, also stimulates the uptake of glucose in hippocampal slices of middle-aged mice, an effect that was again prevented by AM630. However, we found the levels of the endocannabinoid, anandamide reduced in the hippocampus of TgAPP-2576 mice (a model of β-amyloidosis), and likely as a consequence, COX-2 inhibition failed to stimulate glucose uptake in these mice. Together, these results reveal a novel general glucoregulatory role for CB2Rs in the brain, raising therapeutic interest in CB2R agonists as nootropic agents.

Protective role of cannabinoid CB1 receptors and vascular effects of chronic administration of FAAH inhibitor URB597 in DOCA-salt hypertensive rats

AimsThis study examined whether the fall in blood pressure (BP) induced by the chronic inhibition of fatty acid amide hydrolase (FAAH) by URB597 in deoxycorticosterone acetate (DOCA-salt) hypertensive rats correlates with endocannabinoid-mediated vascular changes. Main methodsFunctional studies were performed in isolated endothelium-intact aortas and small mesenteric arteries (sMAs) using organ bath technique and wire myography, respectively. Key findingsIn the DOCA-salt rats, methanandamide-stimulated relaxation was enhanced in sMAs or diminished in aortas. Its vasorelaxant effect in sMAs was sensitive to the antagonist of the Transient Receptor Potential Vanilloid type 1 (TRPV1), capsazepine, in normo- and hypertensive animals and to the antagonist of the cannabinoid CB1 receptors, AM6545, only in DOCA-salt rats. Cannabinoid CB1 receptors were up-regulated merely in DOCA-salt sMAs. URB597 decreased elevated BP in DOCA-salt rats, medial hypertrophy in DOCA-salt aortas. In sMAs it reduced FAAH expression and restored the augmented phenylephrine-induced contraction in the DOCA-salt rats to the level obtained in normotensive controls. In normotensive rats it diminished endothelium-dependent relaxation and increased phenylephrine-induced contraction. SignificanceThe study showed the protective role of cannabinoid CB1 receptors in DOCA-salt sMAs. Reduction in BP after chronic administration of the FAAH inhibitor URB597 in DOCA-salt hypertensive rats only partially correlates with structural and functional changes in conductance and resistance vessels, respectively. Caution should be taken in studying cannabinoids and FAAH inhibitors as potential therapeutics, because of their vessel- and model-specific activities, and side effects connected with off-target response and activation of alternative pathways of anandamide metabolism.

Major dorsoventral differences in the modulation of the local CA1 hippocampal network by NMDA, mGlu5, adenosine A2A and cannabinoid CB1 receptors

Recent research points to diversification in the local neuronal circuitry between dorsal (DH) and ventral (VH) hippocampus that may be involved in the large-scale functional segregation along the long axis of the hippocampus. Here, using CA1 field recordings from rat hippocampal slices, we show that activation of N-methyl-d-aspartate receptors (NMDARs) reduced excitatory transmission more in VH than in DH, with an adenosine A1 receptor-independent mechanism, and reduced inhibition and enhanced postsynaptic excitability only in DH. Strikingly, co-activation of metabotropic glutamate receptor-5 (mGluR5) with NMDAR, by CHPG and NMDA respectively, strongly potentiated the effects of NMDAR in DH but had not any potentiating effect in VH. Furthermore, the synergistic actions in DH were occluded by blockade of adenosine A2A receptors (A2ARs) by their antagonist ZM 241385 demonstrating a tonic action of these receptors in DH. Exogenous activation of A2ARs by 4-[2-[[6-amino-9-(N-ethyl-β-D-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl]benzenepropanoic acid hydrochloride (CGS 21680) did not change the effects of mGluR5–NMDAR co-activation in either hippocampal pole. Importantly, blockade of cannabinoid CB1 receptors (CB1Rs) by their antagonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide (AM 281) restricted the synergistic actions of mGluR5–NMDARs on excitatory synaptic transmission and postsynaptic excitability and abolished their effect on inhibition. Furthermore, AM 281 increased the excitatory transmission only in DH indicating that CB1Rs were tonically active in DH but not VH. Removing the magnesium ions from the perfusion medium neither stimulated the interaction between mGluR5 and NMDAR in VH nor augmented the synergy of the two receptors in DH. These findings show that the NMDAR-dependent modulation of fundamental parameters of the local neuronal network, by mGluR5, A2AR and CB1R, markedly differs between DH and VH. We propose that the higher modulatory role of A2AR and mGluR5, in combination with the role of CB1Rs, provide DH with higher functional flexibility of its NMDARs, compared with VH.

SY21-2ROLE OF CANNABINOID CB2 RECEPTOR IN THE REINFORCING ACTIONS OF ETHANOL

Background. In recent years, a number of studies have suggested a close interaction between the endocannabinoid system and ethanol-related behaviors. Several studies have proposed that the cannabinoid CB2 receptor (CB2r) plays a relevant role in the neurobiology of substance abuse. This study examines the role of CB2r on …

P.5.d.005 Role of cannabinoid CB2 receptor in Parkinson's disease

Parkinson’s disease is a second most common age-related neurodegenerative disorder characterized by the loss of DA neurons of SNpc region of the midbrain. Neurotransmitter dysfunction is involved in the pathogenesis of PD. Antidepressants like venlafaxine and sertraline expected to improve Parkinsonism like symptoms by modulating the levels of various neurotransmitters. The neuroprotective role of antidepressants is well explored in various CNS disorders. Therefore, this study was designed to explore and compare the mechanistic role of different antidepressants (venlafaxine and sertraline) against rotenone induced Parkinsonism like symptoms in rats. Rats were administrated with rotenone (1.5 mg/kg/day; s.c.) daily for a period of 28 days. Venlafaxine (10 and 20 mg/kg; p.o.), sertraline (10 and 20 mg/kg; p.o.) and Levodopa combination with Carbidopa (10 mg/kg; p.o.) were administered daily starting from 7th day one hour prior to rotenone administration. Behavioral parameters (body weight, rotarod, grip strength, narrow beam walk and open field) were assessed on weekly basis. On 28th day, animals were sacrificed and striatum were isolated for biochemical (LPO, GSH and nitrite), neuroinflammatory (TNF-α, IL-1β and IL-6), neurochemical (DA, NE, 5-HT, GABA, Glutamate, DOPAC, HVA and 5-HIAA) and mitochondrial complex-I estimation. Rotenone administration significantly reduced body weight, motor coordination, oxidative defense, increased pro-inflammatory mediators and decreased level of catecholamines. Pre-treatment with venlafaxine and sertraline significantly attenuated the alteration in behavioral, oxidative stress, neuroinflammatory, mitochondrial and catecholamines level in striatum. The study provides a hope that these drugs could be used as adjuvant therapy in the management and treatment of PD.

Spinal Cord is the Primary Site of Action of the Cannabinoid CB2 Receptor Agonist JWH133 that Suppresses Neuropathic Pain: Possible Involvement of Microglia

Neuropathic pain, a highly debilitating condition that commonly occurs after damage to the nervous system, is often resistant to commonly used analgesic agents such as non-steroidal anti-inflammatory drugs and even opioids.Several studies using rodent models reported that cannabinoid CB2 receptor (CB2R) agonists are effective for treating chronic pain. However, the analgesic mechanism of CB2R agonists in neuropathic pain states is not fully understood. In this study, we investigated the role of CB2Rs in the development and maintenance phases of neuropathic pain, and the mechanism of the CB2R-mediated analgesic effect on neuropathic pain. In a rat model of neuropathic pain, systemic administration of JWH133, a CB2R agonist, markedly improved tactile allodynia, and this effect was prevented by intrathecal pretreatment with AM630, a CB2R antagonist. The antiallodynic effect of intrathecally administered JWH133 was inhibited by intrathecal pretreatment with pertussis toxin or forskolin. In the spinal cord, CB2R expression was significantly increased on post-operative day 3, and persisted for 2 weeks. Furthermore, repeated intrathecal administration of JWH133 notably attenuated the development of tactile allodynia after peripheral nerve injury. In a culture of microglia activated by overexpressing interferon regulatory factor 8, a transcription factor crucial for neuropathic pain, JWH133 treatment suppressed the increased expression of interleukin-1β. Our findings suggest that activation of CB2Rs upregulated in the spinal cord after nerve injury alleviates existing tactile allodynia through the Gi/oadenylate cyclase signaling pathway and suppresses the development of allodynia. This process may reduce the inflammatory response of microglia. Therefore, spinal CB2Rs may be a therapeutic target for the treatment of neuropathic pain.

New horizons on the role of cannabinoid CB1 receptors in palatable food intake, obesity and related dysmetabolism.

Excessive consumption of high-energy, palatable food contributes to obesity, which results in the metabolic syndrome, heart disease, type-2 diabetes and death. Current knowledge on the function of the hypothalamus as the brain 'feeding centre' recognizes this region as the main regulator of body weight in the central nervous system. Because of their intrinsically fast and adaptive activities, feeding-controlling neural circuitries are endowed with synaptic plasticity modulated by neurotransmitters and hormones that act at different hierarchical levels of integration. In the hypothalamus, among the chemical mediators involved in this integration, endocannabinoids (eCBs) are ideal candidates for the fast (that is, non-genomic), stress-related fine-tuning of neuronal functions. In this article, we overview the role of the eCB system (ECS) in the control of energy intake, and particularly in the consumption of high-energy, palatable food, and discuss how such a role is affected in the brain by changes in the levels of feeding-regulated hormones, such as the adipose tissue-derived anorexigenic mediator leptin, as well as by high-fat diets. The understanding of the molecular mechanisms underlying the neuronal control of feeding behaviours by eCBs offers many potential opportunities for novel therapeutic approaches against obesity. Highlights of the latest advances in the development of strategies that minimize central ECS overactivity in 'western diet'-driven obesity are discussed.

Regulatory role of the cannabinoid CB2 receptor in stress‐induced neuroinflammation in mice

Stress exposure produces excitotoxicity and neuroinflammation, contributing to the cellular damage observed in stress-related neuropathologies. The endocannabinoids provide a homeostatic system, present in stress-responsive neural circuits. Here, we have assessed the possible regulatory role of cannabinoid CB2 receptors in stress-induced excitotoxicity and neuroinflammation. We used wild type (WT), transgenic overexpressing CB2 receptors (CB2xP) and CB2 receptor knockout (CB2-KO) mice exposed to immobilization and acoustic stress (2 h·day(-1) for 4 days). The CB2 receptor agonist JWH-133 was administered daily (2 mg·kg(-1), i.p.) to WT and CB2-KO animals. Glutamate uptake was measured in synaptosomes from frontal cortex; Western blots and RT-PCR were used to measure proinflammatory cytokines, enzymes and mediators in homogenates of frontal cortex. Increased plasma corticosterone induced by stress was not modified by manipulating CB2 receptors. JWH-133 treatment or overexpression of CB2 receptors increased control levels of glutamate uptake, which were reduced by stress back to control levels. JWH-133 prevented the stress-induced increase in proinflammatory cytokines (TNF-α and CCL2), in NF-κB, and in NOS-2 and COX-2 and in the consequent cellular oxidative and nitrosative damage (lipid peroxidation). CB2xP mice exhibited anti-inflammatory or neuroprotective actions similar to those in JWH-133 pretreated animals. Conversely, lack of CB2 receptors (CB2-KO mice) exacerbated stress-induced neuroinflammatory responses and confirmed that effects of JWH-133 were mediated through CB2 receptors. Pharmacological manipulation of CB2 receptors is a potential therapeutic strategy for the treatment of stress-related pathologies with a neuroinflammatory component, such as depression.

CB1 cannabinoid receptors are involved in neuroleptic-induced enhancement of brain neurotensin.

Objective(s ): Targeting the neuropeptide systems has been shown to be useful for the development of more effective antipsychotic drugs. Neurotensin, an endogenous neuropeptide, appears to be involved in the mechanism of action of antipsychotics. However, the available data provide conflicting results and the mechanism(s) by which antipsychotics affect brain neurotensin neurotransmission have not been identified. Therefore, we aimed to investigate the effects of fluphenazine and amisulpride on brain regional contents of neurotensin considering the role of cannabinoid CB1 receptors which interact with neurotensin neurotransmission. Fluphenazine (0.5, 1, and 3 mg/kg) or amisulpride (3, 5, and 10 mg/kg) were administered intraperitoneally to male Wistar rats either for one day or 28 consecutive days. Twenty four hours after the last injection of drug or vehicle, neurotensin contents were determined in the mesocorticolimbic and nigrostriatal dopamine regions by radioimmunoassay. In the case of any significant change, the effect of pre-treatment with CB1 receptor antagonist, AM251 was investigated. Chronic, but not acute, treatment with the highest dose of fluphenazine or amisulpride resulted in significant enhancement of neurotensin contents in the prefronatal cortex and nucleus accumbens. Fluphenazine also elevated neurotensin levels in the anterior and posterior caudate nuclei and substantia nigra. Neither amisulpride nor fluphenazine affected neurotensin contents in the amygdala or hippocampus. Pre-treatment with AM251 (3 mg/kg) prevented the neuroleptic-induced elevation of neurotensin. AM251 showed no effect by itself. The brain neurotensin under the regulatory action of CB1 receptors is involved in the effects of amisulpride and fluphenazine.

P.1.g.040 Role of cannabinoid CB1 receptors in modulation of dopamine output in the prefrontal cortex associated with food restriction in rats

P.1.g.040 Role of cannabinoid CB1 receptors in modulation of dopamine output in the prefrontal cortex associated with food restriction in rats

P.1.g.036 Role of cannabinoid CB1 receptor in the regulation of aggressive social behaviour

P.1.g.036 Role of cannabinoid CB1 receptor in the regulation of aggressive social behaviour

CB1 cannabinoid receptor-mediated aggressive behavior

This study examined the role of cannabinoid CB1 receptors (CB1r) in aggressive behavior. Social encounters took place in grouped and isolated mice lacking CB1r (CB1KO) and in wild-type (WT) littermates. Cognitive impulsivity was evaluated in the delayed reinforcement task (DRT). Gene expression analyses of monoaminooxidase-A (MAO-A), catechol-o-methyl-transferase (COMT), 5-hydroxytriptamine transporter (5-HTT) and 5-HT1B serotonergic receptor (5HT1Br) in the median and dorsal raphe nuclei (MnR and DR, respectively) and in the amygdala (AMY) were performed by real time-PCR. Double immunohistochemistry studies evaluated COMT and CB1r co-localization in the raphe nuclei and in the cortical (ACo), basomedian (BMA) and basolateral (BLA) amygdaloid nuclei. The behavioral effects of the CB1r agonist ACEA (1 and 2 mg/kg) on aggression were also evaluated in isolated OF1 mice. CB1KO mice housed in groups showed higher levels of offensive aggression. Isolation increased aggressive behavior only in WT. In grouped CB1KO mice COMT gene expression was significantly higher in the MnR and DR, while MAO-A gene expression was lower in the MnR. Gene expression of 5HT1Br, COMT and MAO-A was higher in the amygdala of CB1KO mice. CB1r double-immunohistochemistry revealed cytoplasmic-labeled COMT-ir cells in the raphe nuclei and in the ACo, BMA and BLA. CB1r immunolabeling was observed only in ACo, BMA and BLA, where it was localized in axons and buttons. The density of labeled processes increased in BLA. Acute administration of the CB1 agonist ACEA (2 mg/kg) significantly decreased the aggression levels of OF1 mice. These results suggest that CB1r plays an important role in social interaction and aggressive behavior.