scholarly journals Footshock-Induced Abstinence from Compulsive Methamphetamine Self-administration in Rat Model Is Accompanied by Increased Hippocampal Expression of Cannabinoid Receptors (CB1 and CB2)

Author(s):  
Subramaniam Jayanthi ◽  
Ritvik Peesapati ◽  
Michael T. McCoy ◽  
Bruce Ladenheim ◽  
Jean Lud Cadet

AbstractMethamphetamine (METH) use disorder (MUD) is characterized by compulsive and repeated drug taking despite negative life consequences. Large intake of METH in humans and animals is accompanied by dysfunctions in learning and memory processes. The endocannabinoid system (ECS) is known to modulate synaptic plasticity and cognitive functions. In addition, the ECS has been implicated in some of the manifestations of substance use disorders (SUDs). We therefore sought to identify potential changes in the expression of various enzymes and of the receptors (CB1 and CB2) that are members of that system. Herein, we used a model of METH self-administration (SA) that includes a punishment phase (footshocks) that helps to separate rats into a compulsive METH phenotype (compulsive) that continues to take METH and a non-compulsive METH (abstinent) group that suppressed or stopped taking METH. Animals were euthanized 2 h after the last METH SA session and their hippocampi were used to measure mRNA levels of cannabinoid receptors (CB/Cnr), as well as those of synthesizing (DAGL-A, DAGL-B, NAPEPLD) and metabolizing (MGLL, FAAH, PTGS2) enzymes of the endocannabinoid cascade. Non-compulsive rats exhibited significant increased hippocampal expression of CB1/Cnr1 and CB2/Cnr2 mRNAs. mRNA levels of the synthesizing enzyme, DAGL-A, and of the metabolic enzymes, MGLL and FAAH, were also increased. Non-compulsive rats also exhibited a significant decrease in hippocampal Ptgs2 mRNA levels. Taken together, these observations implicate the hippocampal endocannabinoid system in the suppression of METH intake in the presence of adverse consequences.

2021 ◽  
Vol 354 ◽  
pp. 109110
Author(s):  
E. Andrew Townsend ◽  
Kathryn L. Schwienteck ◽  
Hannah L. Robinson ◽  
Stephen T. Lawson ◽  
Matthew L. Banks

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Saatheeyavaane Bhuvanendran ◽  
Siti Najmi Syuhadaa Bakar ◽  
Yatinesh Kumari ◽  
Iekhsan Othman ◽  
Mohd. Farooq Shaikh ◽  
...  

Abstract Alzheimer’s disease (AD) is the second most occurring neurological disorder after stroke and is associated with cerebral hypoperfusion, possibly contributing to cognitive impairment. In the present study, neuroprotective and anti-AD effects of embelin were evaluated in chronic cerebral hypoperfusion (CCH) rat model using permanent bilateral common carotid artery occlusion (BCCAO) method. Rats were administered with embelin at doses of 0.3, 0.6 or 1.2 mg/kg (i.p) on day 14 post-surgery and tested in Morris water maze (MWM) followed by electrophysiological recordings to access cognitive abilities and synaptic plasticity. The hippocampal brain regions were extracted for gene expression and neurotransmitters analysis. Treatment with embelin at the doses of 0.3 and 0.6 mg/kg significantly reversed the spatial memory impairment induced by CCH in rats. Embelin treatment has significantly protected synaptic plasticity impairment as assessed by hippocampal long-term potentiation (LTP) test. The mechanism of this study demonstrated that embelin treatment alleviated the decreased expression of BDNF, CREB1, APP, Mapt, SOD1 and NFκB mRNA levels caused by CCH rats. Furthermore, treatment with embelin demonstrated neuromodulatory activity by its ability to restore hippocampal neurotransmitters. Overall these data suggest that embelin improve memory and synaptic plasticity impairment in CCH rats and can be a potential drug candidate for neurodegenerative disease-related cognitive disorders.


2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Xue Shen ◽  
Hua Duan ◽  
Sha Wang ◽  
Lu Gan ◽  
Qian Xu ◽  
...  

Objective. Adenomyosis is a common gynecologic benign disease that may have a life-long negative impact on women. Previous studies have indicated that the endocannabinoid system may participate in the progress of endometriosis. Our research aims to analyze the expression patterns of the typical cannabinoid receptors (CB1 and CB2), the main constituents of the endocannabinoid system, in endometrial samples derived from patients diagnosed as adenomyosis or not. Methods. Eutopic and corresponding ectopic endometrium from 45 premenopausal women diagnosed as adenomyosis and normal endometrium from 34 age-matched women lacking evidence of adenomyosis were examined by immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR) to determine the CB1 and CB2 expression levels. Results. In either the proliferative or the secretory phase, CB1 and CB2 protein and mRNA levels were both significantly lower in the eutopic and ectopic endometrium of adenomyosis when compared with normal endometrium. For women with adenomyosis, CB1 and CB2 protein and mRNA levels were much lower in the ectopic endometrium than the eutopic in both phases of the cycle. Both CB1 and CB2 protein and mRNA levels were increased during the secretory phase in normal endometrium, while CB1 lost its cyclic variation in the eutopic and ectopic endometrium from patients diagnosed as adenomyosis. Conclusion. The decreased expression of CB1 and CB2 in the eutopic and ectopic endometrium from patients diagnosed as adenomyosis suggests that cannabinoid receptors may participate in the pathogenesis of adenomyosis.


2021 ◽  
Vol 15 ◽  
Author(s):  
Mark D. Namba ◽  
Jonna M. Leyrer-Jackson ◽  
Erin K. Nagy ◽  
M. Foster Olive ◽  
Janet L. Neisewander

Recent studies examining the neurobiology of substance abuse have revealed a significant role of neuroimmune signaling as a mechanism through which drugs of abuse induce aberrant changes in synaptic plasticity and contribute to substance abuse-related behaviors. Immune signaling within the brain and the periphery critically regulates homeostasis of the nervous system. Perturbations in immune signaling can induce neuroinflammation or immunosuppression, which dysregulate nervous system function including neural processes associated with substance use disorders (SUDs). In this review, we discuss the literature that demonstrates a role of neuroimmune signaling in regulating learning, memory, and synaptic plasticity, emphasizing specific cytokine signaling within the central nervous system. We then highlight recent preclinical studies, within the last 5 years when possible, that have identified immune mechanisms within the brain and the periphery associated with addiction-related behaviors. Findings thus far underscore the need for future investigations into the clinical potential of immunopharmacology as a novel approach toward treating SUDs. Considering the high prevalence rate of comorbidities among those with SUDs, we also discuss neuroimmune mechanisms of common comorbidities associated with SUDs and highlight potentially novel treatment targets for these comorbid conditions. We argue that immunopharmacology represents a novel frontier in the development of new pharmacotherapies that promote long-term abstinence from drug use and minimize the detrimental impact of SUD comorbidities on patient health and treatment outcomes.


Molecules ◽  
2019 ◽  
Vol 24 (6) ◽  
pp. 1125 ◽  
Author(s):  
Beata Bystrowska ◽  
Małgorzata Frankowska ◽  
Irena Smaga ◽  
Ewa Niedzielska-Andres ◽  
Lucyna Pomierny-Chamioło ◽  
...  

There is strong support for the role of the endocannabinoid system and the noncannabinoid lipid signaling molecules, N-acylethanolamines (NAEs), in cocaine reward and withdrawal. In the latest study, we investigated the changes in the levels of the above molecules and expression of cannabinoid receptors (CB1 and CB2) in several brain regions during cocaine-induced reinstatement in rats. By using intravenous cocaine self-administration and extinction procedures linked with yoked triad controls, we found that a priming dose of cocaine (10 mg/kg, i.p.) evoked an increase of the anadamide (AEA) level in the hippocampus and prefrontal cortex only in animals that had previously self-administered cocaine. In the same animals, the level of 2-arachidonoylglycerol (2-AG) increased in the hippocampus and nucleus accumbens. Moreover, the drug-induced relapse resulted in a potent increase in NAEs levels in the cortical areas and striatum and, at the same time, a decrease in the tissue levels of oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) was noted in the nucleus accumbens, cerebellum, and/or hippocampus. At the level of cannabinoid receptors, a priming dose of cocaine evoked either upregulation of the CB1 and CB2 receptors in the prefrontal cortex and lateral septal nuclei or downregulation of the CB1 receptors in the ventral tegmental area. In the medial globus pallidus we observed the upregulation of the CB2 receptor only after yoked chronic cocaine treatment. Our findings support that in the rat brain, the endocannabinoid system and NAEs are involved in cocaine induced-reinstatement where these molecules changed in a region-specific manner and may represent brain molecular signatures for the development of new treatments for cocaine addiction.


2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
J Jehle ◽  
E Avraamidou ◽  
M Danisch ◽  
S Bagheri ◽  
B Schoene ◽  
...  

Abstract Background The endocannabinoid 2-arachidonoylglycerol (2-AG) is an inflammatory mediator and ligand to the cannabinoid receptors CB1 and CB2, which are expressed on myeloid and endothelial cells. 2-AG has recently been described to promote atherogenesis in ApoE-deficient mice. While the CB2 receptor has previously been considered to solely exert anti-inflammatory and atheroprotective effects, newer data have raised the notion, that CB2 might exert atherogenic effects in the context of elevated 2-AG plasma levels. In the present study, we investigated the atherogenic mechanisms of 2-AG and the role of the CB2 receptor on myeloid and endothelial cells in atherogenesis using cell-specific knockout mouse models. Methods Two mouse models with atherogenic background and distinct cell-specific knockouts of the CB2 receptor on myeloid (ApoE−/−LysMcreCB2fl/fl) or endothelial cells (ApoE−/−Tie2creCB2fl/fl) were created. Mice were treated with JZL184, which inhibits 2-AG-degrading enzyme monoacylglycerol lipase, and thereby elevates 2-AG plasma levels, or with vehicle (DMSO), while being fed a high-fat diet for four weeks. Plaque volume and plaque composition were analyzed. In vitro, macrophages were treated with 2-AG and mRNA levels of adhesion molecules, scavenger receptors and chemokines, the production of reactive oxygen species (ROS) and the release of myeloperoxidase (MPO) were determined using qPCR, fluorometric assays and ELISA respectively. Results Elevated levels of 2-AG promote atherogenesis in ApoE-deficient mice (JZL184 vs. DMSO: 39.6±2.1% vs. 32.6±2.4%; n=14; p<0.05). The atherogenic effect of 2-AG is abrogated in mice lacking myeloid CB2 receptor expression (35.0±2.0% vs. 34.0±2.5%; n=14–16; p>0.05) but not in mice lacking endothelial CB2 receptor expression (37.1±3.1% vs. 20.9±2.6%; n=10–12; p<0.01). In vitro, 2-AG significantly increases transcription of adhesion molecule ICAM-1 (2.09±0.42 –fold; n=5–6; p<0.05), chemokine receptor CCR-1 (2.04±0.46 -fold; n=10–11; p<0.05) and scavenger receptor CD36 (8.02±1.89-fold; n=3; p<0.05) in 2-AG-treated macrophages. These effects are mitigated by pharmacological inhibition of CB2. Furthermore, 2-AG significantly increases myeloperoxidase (MPO) release in monocytes in a CB receptor-dependent fashion (451±23 pg/ml vs. 151±8.3 pg/ml; n=3–4; p<0.01) and promotes ROS production (2698±24 pdu vs. 1981±27 pdu; n=8; p<0.01). Conclusion Elevated 2-AG levels show an atherogenic effect in vivo which is dependent on the presence of the CB2 receptor on myeloid cells. Our in vitro data reveal 2-AG to promote pro-inflammatory signaling in macrophages and elucidate a previously unrecognized link between the endocannabinoid system and MPO in monocytes. In summary, cell-specific effects of the endocannabinoid system will have to be taken into account to facilitate its exploitation as an anti-atherosclerotic drug target. Acknowledgement/Funding This work was supported by the Bonfor program of the University of Bonn [grant number O-109.0057 to JJ].


2012 ◽  
Vol 367 (1607) ◽  
pp. 3193-3200 ◽  
Author(s):  
Stephen D. Skaper ◽  
Vincenzo Di Marzo

The psychoactive component of the cannabis resin and flowers, delta9-tetrahydrocannabinol (THC), was first isolated in 1964, and at least 70 other structurally related ‘phytocannabinoid’ compounds have since been identified. The serendipitous identification of a G-protein-coupled cannabinoid receptor at which THC is active in the brain heralded an explosion in cannabinoid research. Elements of the endocannabinoid system (ECS) comprise the cannabinoid receptors, a family of nascent lipid ligands, the ‘endocannabinoids’ and the machinery for their biosynthesis and metabolism. The function of the ECS is thus defined by modulation of these receptors, in particular, by two of the best-described ligands, 2-arachidonoyl glycerol and anandamide (arachidonylethanolamide). Research on the ECS has recently aroused enormous interest not only for the physiological functions, but also for the promising therapeutic potentials of drugs interfering with the activity of cannabinoid receptors. Many of the former relate to stress-recovery systems and to the maintenance of homeostatic balance. Among other functions, the ECS is involved in neuroprotection, modulation of nociception, regulation of motor activity, neurogenesis, synaptic plasticity and the control of certain phases of memory processing. In addition, the ECS acts to modulate the immune and inflammatory responses and to maintain a positive energy balance. This theme issue aims to provide the reader with an overview of ECS pharmacology, followed by discussions on the pivotal role of this system in the modulation of neurogenesis in the developing and adult organism, memory processes and synaptic plasticity, as well as in pathological pain and brain ageing. The volume will conclude with discussions that address the proposed therapeutic applications of targeting the ECS for the treatment of neurodegeneration, pain and mental illness.


Reproduction ◽  
2015 ◽  
Vol 150 (6) ◽  
pp. 463-472 ◽  
Author(s):  
María Victoria Bariani ◽  
Ana Paula Domínguez Rubio ◽  
Maximiliano Cella ◽  
Juliana Burdet ◽  
Ana María Franchi ◽  
...  

Prematurity is the leading cause of perinatal morbidity and mortality worldwide. There is a strong causal relationship between infection and preterm births. Intrauterine infection elicits an immune response involving the release of inflammatory mediators like cytokines and prostaglandins (PG) that trigger uterine contractions and parturition events. Anandamide (AEA) is an endogenous ligand for the cannabinoid receptors CB1 and CB2. Similarly to PG, endocannabinoids are implicated in different aspects of reproduction, such as maintenance of pregnancy and parturition. Little is known about the involvement of endocannabinoids on the onset of labor in an infectious milieu. Here, using a mouse model of preterm labor induced by lipopolysaccharide (LPS), we explored changes on the expression of components of endocannabinoid system (ECS). We have also determined whether AEA and CB antagonists alter PG production that induces labor. We observed an increase in uterineN-acylphosphatidylethanolamine-specific phospholipase D expression (NAPE-PLD, the enzyme that synthesizes AEA) upon LPS treatment. Activity of catabolic enzyme fatty acid amide hydrolase (FAAH) did not change significantly. In addition, we also found that LPS modulated uterine cannabinoid receptors expression by downregulatingCb2mRNA levels and upregulating CB1 protein expression. Furthermore, LPS and AEA induced PGF2a augmentation, and this was reversed by antagonizing CB1 receptor. Collectively, our results suggest that ECS may be involved in the mechanism by which infection causes preterm birth.


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