Neurochemical and Behavioral Characterization after Acute and Repeated Exposure to Novel Synthetic Cannabinoid Agonist 5-MDMB-PICA

Since the early 2000s, herbal mixtures containing synthetic cannabinoids (SCs), broadly known as Spice/K2, have been marketed as a legal marijuana surrogate and have become very popular among adolescents. Adolescence is a critical period of development, which is associated with an increased vulnerability to the central effects of drugs. Despite growing concerns about the negative effects of the use of SCs, newly synthetized compounds are increasingly detected in drugs seized by the authorities, posing a serious threat to public health. 5F-MDMB-PICA has been recently detected and classified as a highly potent agonist of CB1 and CB2 cannabinoid receptors. Here, we first investigated the rewarding properties of 5F-MDMB-PICA in C57BL/6 adolescent and adult mice by in vivo brain microdialysis. Data showed that acute administration of a selected dose of 5F-MDMB-PICA (0.01 mg/kg i.p.) stimulates the release of dopamine in the nucleus accumbens shell of adolescent, but not of adult, mice. To further investigate the consequences of repeated exposure to this dose of 5F-MDMB-PICA, a separate group of adolescent mice was treated for 14 consecutive days and evaluated for behavioral abnormalities at adulthood, starting from 7 days after drug discontinuation. Data showed that this group of adult mice displayed an anxiety-like and compulsive-like state as revealed by an altered performance in the marble burying test. Our study suggests an alarming vulnerability of adolescent mice to the effects of 5F-MDMB-PICA. These findings provide a useful basis for understanding and evaluating both early and late detrimental effects that may derive from the use of SCs during adolescence

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

Effects of Pulverized Burnt Clay Waste Fineness on the Compressive Strength and Durability Properties of Blended Cement Concrete

The search for an alternative binder to cement, partially or wholly, continues to be on the increase. In this study, the fineness of pulverized burnt clay waste was evaluated as a factor that affects the compressive strength, chloride penetration and strength deterioration in sulphuric acid of its blended cement concrete. Pulverized burnt clay waste obtained from a source was divided into two different fineness portions using 75 and 150 µm sieves and classified as fine and coarse portions, respectively. Portland cement was replaced at 10 and 20% by weight with fine and coarse portions, separately. Additional mix containing 105% binder content consisting 5% excess fine and coarse portions at 10 and 20% cement replacement was also included. Chloride penetration was measured using the full immersion technique in 3% sodium chloride solution. The results revealed that increasing the fineness of pulverized burnt clay waste increases the compressive strength, reduced the chloride penetration and improves the acidic resistance of the blended cement concrete. These enhanced properties are due to the improved interfacial zone in the concrete resulting from increased specific surface area of the fine portion. Further improvement of the blended cement concrete properties can also be achieved with the use of 105% binder content containing 5% excess pozzolan beyond the conventional cement replacement level as observed in this study.The search for an alternative binder to cement, partially or wholly, continues to be on the increase. In this study, the fineness of pulverized burnt clay waste was evaluated as a factor that affects the compressive strength, chloride penetration and strength deterioration in sulphuric acid of its blended cement concrete. Pulverized burnt clay waste obtained from a source was divided into two different fineness portions using 75 and 150 µm sieves and classified as fine and coarse portions, respectively. Portland cement was replaced at 10 and 20% by weight with fine and coarse portions, separately. Additional mix containing 105% binder content consisting 5% excess fine and coarse portions at 10 and 20% cement replacement was also included. Chloride penetration was measured using the full immersion technique in 3% sodium chloride solution. The results revealed that increasing the fineness of pulverized burnt clay waste increases the compressive strength, reduced the chloride penetration and improves the acidic resistance of the blended cement concrete. These enhanced properties are due to the improved interfacial zone in the concrete resulting from increased specific surface area of the fine portion. Further improvement of the blended cement concrete properties can also be achieved with the use of 105% binder content containing 5% excess pozzolan beyond the conventional cement replacement level as observed in this study

Cannabinoid CB2 Receptor Gene and Environmental Interaction in the Development of Psychiatric Disorders

CB2 cannabinoid receptor (CB2R) gene is associated with depression. We investigated the gene-environment interaction between CB2R function and diverse stressors. First, anxiety-like behavior during chronic-mild-stress (CMS) was evaluated in C57BL/6JJmsSlc mice following treatment with CB2R agonist JWH015 or inverse-agonist AM630. Second, locomotor activity and anxiety-like behavior were measured following exposure to an immune poly I:C stressor. Gene expressions of HPA axis related molecules, Fkbp5, Nr3c1 and Crf and pro-inflammatory cytokine Il-1b, as well as Bdnf as a key neurotrophin that supports neuron health, function, and synaptic plasticity, were determined in hippocampus of Cnr2 knockout mice, as indicators of stressful environment. CMS-induced anxiety-like behavior was enhanced by AM630 and reduced by JWH015 and fluvoxamine. Poly I:C reduced locomotor activity and increased anxiety-like behavior, and these effects were pronounced in the heterozygote than in the wild type mice. Fkbp5 and Nr3c1 expression were lower in the Cnr2 heterozygotes than in the wild type mice with Poly I:C treatment. These findings indicate that interaction between CB2R gene and stressors increases the risk of depression-like behaviors that may be linked with neuro-immune crosstalk. Further studies in human subjects are necessary to determine the role of CB2R and environmental interaction in the development of depression