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Victoria S Cavener, Andrew Gaulden, Dante Pennipede, Puja Jagasia, Jashim Uddin, Lawrence J Marnett, Sachin Patel
Elucidating the underlying molecular mechanisms regulating fear and extinction learning may offer insights that can lead to novel treatments for debilitating anxiety and trauma-related disorders including posttraumatic stress disorder. The endocannabinoid (eCB) system is a retrograde inhibitory signaling pathway involved in regulating central responses to stress. The eCB 2-arachidonoylglycerol (2-AG) has recently been proposed to serve as a homeostatic signal mitigating adverse effects of stress exposure, however, less well understood is 2-AG's role in fear learning and fear extinction...
2018: Frontiers in Neuroscience
Roberta Imperatore, Livia D'Angelo, Omid Safari, Hamidreza Ahmadniaye Motlagh, Fabiana Piscitelli, Paolo de Girolamo, Luigia Cristino, Ettore Varricchio, Vincenzo di Marzo, Marina Paolucci
Hypocretins/Orexins neuropeptides are known to regulate numerous physiological functions, such as energy homeostasis, food intake, sleep/wake cycle, arousal and wakefulness, in vertebrates. Previous studies on mice have revealed an intriguing orexins/endocannabinoids (ECs) signaling interaction at both structural and functional levels, with OX-A behaving as a strong enhancer of 2-arachydonoyl-glycerol (2-AG) biosynthesis. In this study, we describe, for the first time in the brain of zebrafish, the anatomical distribution and co-expression of orexin (OX-2R) and endocannabinoid (CB1R) receptors, suggesting a functional interaction...
2018: Frontiers in Neuroanatomy
Ryan R Wyrofsky, Beverly A S Reyes, Daohai Yu, Lynn G Kirby, Elisabeth J Van Bockstaele
Cannabinoids are capable of modulating mood, arousal, cognition, and behavior, in part via their effects on the noradrenergic nucleus locus coeruleus (LC). Dysregulation of LC signaling and norepinephrine (NE) efflux in the medial prefrontal cortex (mPFC) can lead to the development of psychiatric disorders, and CB1r deletion results in alterations of α2- and β1-adrenoceptors in the mPFC, suggestive of increased LC activity. To determine how CB1r deletion alters LC signaling, whole-cell patch-clamp electrophysiology was conducted in LC-NE neurons of male and female wild type (WT) and CB1r-knock out (KO) mice...
August 13, 2018: European Journal of Neuroscience
Margherita Brindisi, Giuseppe Borrelli, Simone Brogi, Alessandro Grillo, Samuele Maramai, Marco Paolino, Mascia Benedusi, Alessandra Pecorelli, Giuseppe Valacchi, Lorenzo Di Cesare Mannelli, Carla Ghelardini, Marco Allarà, Alessia Ligresti, Patrizia Minetti, Giuseppe Campiani, Stefania Butini, Vincenzo di Marzo, Sandra Gemma
The unique role of fatty acid amide hydrolase (FAAH) in terminating endocannabinoid (EC) signaling supports its relevance as therapeutic target. Inhibition of the ECs metabolizing enzymes elicits indirect agonism of CBRs, and therapeutic efficacy, devoid of psychotropic effects. Based on our previous ligands and aiming at discovering new selective FAAH inhibitors, we developed a series of new compounds (5a-l) characterized by functionalized tricyclic scaffolds. All the developed compounds display negligible activity on MAGL and CBRs...
August 7, 2018: ChemMedChem
Shivakumar Subbanna, Vikram Joshi, Balapal S Basavarajappa
Postnatal ethanol exposure has been shown to cause persistent defects in hippocampal synaptic plasticity and disrupt learning and memory processes. However, the mechanisms responsible for these abnormalities are less well studied. We evaluated the influence of postnatal ethanol exposure on several signaling and epigenetic changes and on expression of the activity-regulated cytoskeletal (Arc) protein in the hippocampus of adult offspring under baseline conditions and after a Y-maze spatial memory (SP) behavior (activity)...
July 20, 2018: Neuroscience
Brenda Sbarski, Irit Akirav
Chronic direct activation of cannabinoid CB1 receptors (CB1r) may lead to downregulation of CB1r which may in turn result in a depression-like phenotype in certain individuals. We examined the effects of chronic cannabinoid receptor activation before exposure to an emotional traumatic event on CB1r expression in the basolateral amygdala (BLA) and CA1 and on protracted anxiety- and depression-like behaviors. We used exposure to severe shock and situational reminders (SRs) in an inhibitory apparatus as a model for emotional trauma...
June 29, 2018: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
Rodolfo Sánchez-Zavaleta, Hernán Cortés, José Arturo Avalos-Fuentes, Ubaldo García, José Segovia Vila, David Erlij, Benjamín Florán
Recent studies suggested the expression of CB2 receptors in neurons of the CNS, however, most of these studies have only explored one aspect of the receptors, i.e., expression of protein, messenger RNA, or functional response, and more complete studies appear to be needed to establish adequately their role in the neuronal function. Electron microscopy studies showed the presence of CB2r in asymmetric terminals of the substantia nigra pars reticulata (SNr), and its mRNA appeared is expressed in the subthalamic nucleus...
July 19, 2018: Synapse
Yaochen Zhang, Don-Kyu Kim, Yoon Seok Jung, Yong-Hoon Kim, Yong Soo Lee, Jina Kim, Won-Il Jeong, In-Kyu Lee, Sung Jin Cho, Steven Dooley, Chul-Ho Lee, Hueng-Sik Choi
Upon liver intoxication with malnutrition or high-fat diet feeding, fibrinogen is synthesized by hepatocytes and secreted into the blood in human and mouse. Its primary function is to occlude blood vessels upon damage and thereby stop excessive bleeding. High fibrinogen levels may contribute to the development of pathological thrombosis, which is one mechanism linking fatty liver disease with cardiovascular disease. Our previous results present ERRγ as key regulator of hepatocytic fibrinogen gene expression in human...
July 17, 2018: Archives of Toxicology
Guoxiang Fang, Ying Wang
Depression is a common mental disorder in adolescents, with a prevalence rate of 5.6%. Current anti-depressive options for adolescents are limited: psychological intervention and conventional antidepressants have low efficacy, a delayed onset of action and increased possibility of suicidal risk. Repetitive transcranial magnetic stimulation (rTMS) as an effective and noninvasive physical therapy for adult depression has been investigated in recent years. However, whether it also produces similar effects on juvenile depression and the underlying mechanism are not clearly understood...
July 9, 2018: Neurochemical Research
Yatendra Mulpuri, Vincent N Marty, Joseph J Munier, Ken Mackie, Brian L Schmidt, Herbert H Seltzman, Igor Spigelman
Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and dose-limiting side effect of cancer treatment that affects millions of cancer survivors throughout the world and current treatment options are extremely limited by their side effects. Cannabinoids are highly effective in suppressing pain symptoms of chemotherapy-induced and other peripheral neuropathies but their widespread use is limited by central nervous system (CNS)-mediated side effects. Here, we tested one compound from a series of recently developed synthetic peripherally restricted cannabinoids (PRCBs) in a rat model of cisplatin-induced peripheral neuropathy...
September 1, 2018: Neuropharmacology
Mylyne Tham, Orhan Yilmaz, Mariam Alaverdashvili, Melanie E M Kelly, Eileen M Denovan-Wright, Robert B Laprairie
BACKGROUND AND PURPOSE: We sought to understand why (-)-cannabidiol (CBD) and (-)-cannabidiol-dimethylheptyl (CBD-DMH) exhibit distinct pharmacology, despite near identical structures. EXPERIMENTAL APPROACH: HEK293A cells expressing either human type 1 cannabinoid (CB1 ) receptors or CB2 receptors were treated with CBD or CBD-DMH with or without the CB1 and CB2 receptor agonist CP55,940, CB1 receptor allosteric modulator Org27569 or CB2 receptor inverse agonist SR144528...
July 7, 2018: British Journal of Pharmacology
Adam B Steinmetz, John H Freeman
Systemic administration of cannabinoid agonists impairs cerebellum-dependent motor learning. The cannabinoid-induced impairment of motor learning has been hypothesized to be due to disruption of Purkinje cell plasticity within the cerebellar cortex. In the current study, we tested this hypothesis in rats with localized microinfusions of cannabinoid agonists and antagonists into the cerebellar cortex during eyeblink conditioning, a type of cerebellum-dependent motor learning. Infusions of the cannabinoid agonists WIN55,212-2 or ACEA directly into the eyeblink conditioning microzone of the cerebellar cortex severely impaired acquisition of eyeblink conditioning, whereas the CB1R antagonist SR141716A did not produce a significant impairment...
June 30, 2018: Neurobiology of Learning and Memory
Jenny Ceccarini, Rawaha Ahmad, Laura Van de Vliet, Cindy Casteels, Mathieu Vandenbulcke, Wim Vandenberghe, Koen Van Laere
Many Huntington disease (HD) mutation carriers already have cognitive and psychiatric symptoms in the premanifest (premotor) phase of the disease, but the molecular underpinnings of these symptoms are not well understood. Previous work has shown reduced availability of the cerebral type 1 cannabinoid receptor (CB1 R) in manifest HD. Here, we investigated whether CB1 R binding is related to cognitive and psychiatric symptoms in premanifest HD mutation carriers (preHD). Methods: CB1R binding was measured with 18 F-MK-9470 PET in 15 preHD subjects (8M/7F; age 39...
June 22, 2018: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Alessia Corrado, Monica Battle, Sarah K Wise, F Eun-Hyung Lee, David M Guidot, John M DelGaudio, Samuel A Molina, Joshua M Levy
BACKGROUND: The endocannabinoid system represents a highly conserved, innate signaling network with direct and indirect control of eicosanoid-mediated inflammation. Activation of the type 2 cannabinoid receptor (CB2R) leads to decreased type 2 inflammation and reduced production of arachidonic acid (AA). Given that altered AA metabolism is associated with aspirin-exacerbated respiratory disease (AERD), we hypothesized that expression of the CB2R gene CNR2 is increased in AERD. METHODS: Nasal polyps from consecutive patients undergoing endoscopic sinus surgery for AERD or allergic fungal rhinosinusitis (AFRS) were prospectively evaluated...
June 13, 2018: International Forum of Allergy & Rhinology
Ryan Kucera, Joseph Bouskila, Laurent Elkrief, Anders Fink-Jensen, Roberta Palmour, Jean-François Bouchard, Maurice Ptito
Extensive rodent literature suggests that the endocannabinoid (eCB) system present in the nucleus accumbens (NAc) modulates dopamine (DA) release in this area. However, expression patterns of the cannabinoid receptor type 1 (CB1R), the synthesizing enzyme N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD), and the degradation enzyme fatty acid amide hydrolase (FAAH) in the NAc have not yet been described in non-human primates. The goal of this study is therefore to characterize the expression and localization of the eCB system within the NAc of vervet monkeys (Chlorocebus sabaeus) using Western blots and immunohistochemistry...
June 6, 2018: Scientific Reports
Andrea Chicca, Chiara Arena, Simone Bertini, Francesca Gado, Elena Ciaglia, Mario Abate, Maria Digiacomo, Margherita Lapillo, Giulio Poli, Maurizio Bifulco, Marco Macchia, Tiziano Tuccinardi, Jürg Gertsch, Clementina Manera
The endocannabinoid system (ECS) represents one of the major neuromodulatory systems involved in different physiological and pathological processes. Multi-target compounds exert their activities by acting via multiple mechanisms of action and represent a promising pharmacological modulation of the ECS. In this work we report 4-substituted and 4,5-disubstituted 1,2-dihydro-2-oxo-pyridine-3-carboxamide derivatives with a broad spectrum of affinity and functional activity towards both cannabinoid receptors and additional effects on the main components of the ECS...
June 25, 2018: European Journal of Medicinal Chemistry
Hong Zhang, Dominique M Lund, Haley A Ciccone, William D Staatz, Mohab M Ibrahim, Tally M Largent-Milnes, Herbert H Seltzman, Igor Spigelman, Todd W Vanderah
Many malignant cancers, including breast cancer, have a propensity to invade bones, leading to excruciating bone pain. Opioids are the primary analgesics used to alleviate this cancer-induced bone pain (CIBP) but are associated with numerous severe side effects, including enhanced bone degradation, which significantly impairs patients' quality of life. By contrast, agonists activating only peripheral CB1 receptors (CB1Rs) have been shown to effectively alleviate multiple chronic pain conditions with limited side effects, yet no studies have evaluated their role(s) in CIBP...
May 16, 2018: Pain
Jimena Laura Frontera, Victoria María Gonzalez Pini, Fernando Luis Messore, Alicia Brusco
The endocannabinoid (eCB) system is involved in the modulation of the reward system and participates in the reinforcing effects of different drugs of abuse, including alcohol. The most abundant receptor of the eCB system in the central nervous system is the CB1 receptor (CB1R), which is predominantly expressed in areas involved in drug addiction, such as the nucleus accumbens, the ventral tegmental area, the substantia nigra and the raphe nucleus. CB1R is expressed in early stages during development, and reaches maximum levels during early adolescence...
July 15, 2018: Neuropharmacology
Ji H Han, Hanho Shin, Jun G Rho, Jung-Eun Kim, Dong H Son, Juhwan Yoon, Yong J Lee, Jung-Hyuck Park, Byung J Song, Chang-Sik Choi, Seul G Yoon, Il Y Kim, Eun K Lee, Je K Seong, Ki W Kim, Wook Kim
AIM: To analyze the metabolic parameters and adipose tissue inflammation via NLRP3 inflammasome following chronic treatment of mouse models of obesity with AJ5018 as the peripherally restricted cannabinoid 1 receptor (CB1R) antagonist. MATERIALS AND METHODS: The selectivity for CB1R over CB2R, brain/plasma concentration ratio, and centrally mediated neurobehavioural effects of AJ5018, were assessed. The long-term effects of AJ5018 and rimonabant on the metabolic parameters and adipose tissue inflammation were analyzed in diet-induced obese (DIO) mice and diabetic db/db mice...
May 8, 2018: Diabetes, Obesity & Metabolism
Felipe V Gomes, Jessica R Edelson, David W Volk, Anthony A Grace
Altered cannabinoid 1 receptor (CB1R) expression has been reported in the brain of subjects with schizophrenia, a developmental mental illness that usually emerges in late adolescence/early adulthood. However, the developmental period at which changes in the CB1R expression appear in schizophrenia is unknown. To gain insight into this factor, we assessed the postnatal developmental trajectory of CB1R expression in the methylazoxymethanol (MAM) model of schizophrenia. Using in situ hybridization with film and grain analyses, CB1R messenger RNA (mRNA) levels were quantified in multiple brain regions, including the medial prefrontal cortex (mPFC), secondary motor cortex, dorsomedial and dorsolateral striatum, dorsal subregions and ventral subiculum of the hippocampus, of MAM-treated rats and normal controls at three developmental periods [juvenile - postnatal day (PD) 30; adolescence - PD45; and adulthood - PD85]...
April 26, 2018: Schizophrenia Research
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