Brain Neuronal CB2 Cannabinoid Receptors in Drug Abuse and Depression: From Mice to Human Subjects

BACKGROUND: Addiction and major depression are mental health problems associated with stressful events in life with high relapse and reoccurrence even after treatment. Many laboratories were not able to detect the presence of cannabinoid CB2 receptors (CB2-Rs) in healthy brains, but there has been demonstration of CB2-R expression in rat microglial cells and other brain associated cells during inflammation. Therefore, neuronal expression of CB2-Rs had been ambiguous and controversial and its role in depression and substance abuse is unknown. METHODOLOGY/PRINCIPAL FINDINGS: In this study we tested the hypothesis that genetic variants of CB2 gene might be associated with depression in a human population and that alteration in CB2 gene expression may be involved in the effects of abused substances including opiates, cocaine and ethanol in rodents. Here we demonstrate that a high incidence of (Q63R) but not (H316Y) polymorphism in the CB2 gene was found in Japanese depressed subjects. CB2-Rs and their gene transcripts are expressed in the brains of naïve mice and are modulated following exposure to stressors and administration of abused drugs. Mice that developed alcohol preference had reduced CB2 gene expression and chronic treatment with JWH015 a putative CB2-R agonist, enhanced alcohol consumption in stressed but not in control mice. The direct intracerebroventricular microinjection of CB2 anti-sense oligonucleotide into the mouse brain reduced mouse aversions in the plus-maze test, indicating the functional presence of CB2-Rs in the brain that modifies behavior. We report for the using electron microscopy the sub cellular localization of CB2-Rs that are mainly on post-synaptic elements in rodent brain. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate the functional expression of CB2-Rs in brain that may provide novel targets for the effects of cannabinoids in depression and substance abuse disorders beyond neuro-immunocannabinoid activity

A History of Drug Discovery for Treatment of Nausea and Vomiting and the Implications for Future Research.

The origins of the major classes of current anti-emetics are examined. Serendipity is a recurrent theme in discovery of their anti-emetic properties and repurposing from one indication to another is a continuing trend. Notably, the discoveries have occurred against a background of company mergers and changing anti-emetic requirements. Major drug classes include: (i) Muscarinic receptor antagonists-originated from historical accounts of plant extracts containing atropine and hyoscine with development stimulated by the need to prevent sea-sickness among soldiers during beach landings; (ii) Histamine receptor antagonists-searching for replacements for the anti-malaria drug quinine, in short supply because of wartime shipping blockade, facilitated the discovery of histamine (H1) antagonists (e.g., dimenhydrinate), followed by serendipitous discovery of anti-emetic activity against motion sickness in a patient undergoing treatment for urticaria; (iii) Phenothiazines and dopamine receptor antagonists-investigations of their pharmacology as "sedatives" (e.g., chlorpromazine) implicated dopamine receptors in emesis, leading to development of selective dopamine (D2) receptor antagonists (e.g., domperidone with poor ability to penetrate the blood-brain barrier) as anti-emetics in chemotherapy and surgery; (iv) Metoclopramide and selective 5-hydroxytryptamine3(5-HT3) receptor antagonists-metoclopramide was initially assumed to act only via D2 receptor antagonism but subsequently its gastric motility stimulant effect (proposed to contribute to the anti-emetic action) was shown to be due to 5-hydroxytryptamine4 receptor agonism. Pre-clinical studies showed that anti-emetic efficacy against the newly-introduced, highly emetic, chemotherapeutic agent cisplatin was due to antagonism at 5-HT3 receptors. The latter led to identification of selective 5-HT3 receptor antagonists (e.g., granisetron), a major breakthrough in treatment of chemotherapy-induced emesis; (v) Neurokinin1receptor antagonists-antagonists of the actions of substance P were developed as analgesics but pre-clinical studies identified broad-spectrum anti-emetic effects; clinical studies showed particular efficacy in the delayed phase of chemotherapy-induced emesis. Finally, the repurposing of different drugs for treatment of nausea and vomiting is examined, particularly during palliative care, and also the challenges in identifying novel anti-emetic drugs, particularly for treatment of nausea as compared to vomiting. We consider the lessons from the past for the future and ask why there has not been a major breakthrough in the last 20 years

Mondialisation formation et développement dans les pays du Nord et du Sud

Dans un contexte de mondialisation, où l’économie, les évolutions politiques et socioculturelles jouent un rôle déterminant, les pratiques de formation des enseignants doivent être renouvelées pour répondre aux attentes de la société et en faisant une part importante à la professionnalisation.In the context of globalisation, in which the economy and political and socio-cultural changes play a major part, practises in teacher training must be renewed to respond to what society expects, insisting more particularly on professionalisation.En un contexto de mundialización, en el que la economia, las evolu-ciones politicas y socioculturales desempenan un papel determinante, las prâcticas de formación de los docentes deben renovarse para responder a las esperas de la sociedad otorgándole un lugar importante a la profesionalización

Progress Towards a Library of Potential Fungicides

Methionine Synthase (MetSyn) is an enzyme that uses folate and homocysteine to create the amino acid methionine, which is essential for all organisms. There are key differences between the fungal MetSyn enzyme and the mammalian (human) form, especially with regard to the proximity of the two binding sites for folate and homocysteine. Taking advantage of these differences, an antifungal drug could be developed to exclusively bind the fungal enzyme and inhibit fungal growth while leaving the host (patient) unaffected. We are currently exploring the synthesis of various molecules that mimic folate, an essential substrate for MetSyn function. We plan to screen these molecules against a multitude of fungal species as well as in an isolated system with the MetSyn enzyme itself

Progress Towards a Library of Potential Fungicides

Methionine Synthase (MetSyn) is an enzyme that uses folate and homocysteine to create the amino acid methionine, which is essential for all organisms. There are key differences between the fungal MetSyn enzyme and the mammalian (human) form, especially with regard to the proximity of the two binding sites for folate and homocysteine. Taking advantage of these differences, an antifungal drug could be developed to exclusively bind the fungal enzyme and inhibit fungal growth while leaving the host (patient) unaffected. We are currently exploring the synthesis of various molecules that mimic folate, an essential substrate for MetSyn function. We plan to screen these molecules against a multitude of fungal species as well as in an isolated system with the MetSyn enzyme itself

Micro-Aircraft Design for 2022 SAE AeroDesign Competition

The goal of this project was to design, build and fly a micro remote-controlled aircraft to participate in the 2022 SAE Aero Design West Competition. The competition imposes challenging design constraints on the aircraft which must carry large or small cargo boxes and payload weight while being limited to a 48 inch wingspan, 450 watts of engine power, and an 8 foot takeoff distance from a raised platform. The final design configuration used large wing control surfaces that extended beyond the wing trailing edge to serve as both flaps and ailerons and a movable wing to increase stability. Although the aircraft experienced stability issues on take-off at the SAE micro class competition, the team placed third overall due to high design report and oral presentation scores